Organic compounds

ABSTRACT

The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

The present invention relates generally to the field of inhibitors ofstearoyl-CoA desaturase, such as heterocyclic derivatives, and uses forsuch compounds in treating and/or preventing various human diseases,including those mediated by stearoyl-CoA desaturase (SCD) enzymes,preferably SCD1, especially diseases related to elevated lipid levels,cardiovascular disease, diabetes, obesity, metabolic syndrome,dermatological disorders and the like.

BACKGROUND OF THE INVENTION

Acyl desaturase enzymes catalyze the formation of a double bond in fattyacids derived from either dietary sources or de novo synthesis in theliver. In mammals, at least three fatty acid desaturases exists, eachwith differing specificity: delta-9, delta-6, and delta-5, whichintroduce a double bond at the 9-10, 6-7, and 5-6 positionsrespectively.

Stearoyl-CoA desaturases (SCDs) act with cofactors (other agents) suchas NADPH, cytochrome b5, cytochrome b5 reductase, Fe, and molecular O₂to introduce a double bond into the C9-C10 position (delta 9) ofsaturated fatty acids, when conjugated to Coenzyme A (CoA). Thepreferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0),which are converted to palmitoleoyl-CoA (16:1) and oleyl-CoA (18:1),respectively. The resulting mono-unsaturated fatty acids are substratesfor further metabolism by fatty acid elongases or incorporation intophospholipids, triglycerides, and cholesterol esters. A number ofmammalian SCD genes have been cloned. For example, two genes have beenidentified in humans (hSCD1 and hSCD5) and four SCD genes have beenisolated from mouse (SCD1, SCD2, SCD3, and SCD4). While the basicbiochemical role of SCD has been known in rats and mice since the 1970s(Jeffcoat, R. et al., Eur. J. Biochem. (1979), Vol. 101, No. 2, pp.439-445; de Antueno, R. et al., Lipids (1993), Vol. 28, No. 4, pp.285-290), it has only recently been directly implicated in human diseaseprocesses.

The two human SCD genes have been previously described: hSCD1 byBrownlie et al, PCT published patent application, WO 01/62954, thedisclosure of which is hereby incorporated by reference in its entirety,and hSCD2 by Brownlie, PCT published patent application, WO 02/26944,incorporated herein by reference in its entirety.

To date, the only small-molecule, drug-like compounds known thatspecifically inhibit or modulate SCD activity are found in the followingPCT Published Patent Applications: WO 06/034338, WO 06/034446, WO06/034441, WO 06/034440, WO 06/034341, WO 06/034315, WO 06/034312, WO06/034279, WO 06/014168, WO 05/011657, WO 05/011656, WO 05/011655, WO05/011654, WO 05/011653, WO 06/130986, WO 07/009,236, WO 06/086447, WO06/101521, WO 06/125178, WO 06/125179, WO 06/125180, WO 06/125181, WO06/125194, WO 07/044,085, WO 07/046,867, WO 07/046,868, WO 07/050,124,WO 07/056,846 and WO 07/071,023. SCD inhibitors have also been describedin the following publications: Zhao et al. “Discovery of1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanone stearoyl CoA desaturase1 inhibitors”, Biorg. Med. Chem. Lett., (2007), 17(12), 3388-3391 andLiu et al. “Discovery of potent, orally bioavailable stearoyl-CoAdesaturase 1 inhibitors”, J. Med. Chem., (2007), 50(13), 3086-3100.Before the discovery of the above compounds, only certain long-chainhydrocarbons, analogs of the substrate stearic acid, had been used tostudy SCD activity. Known examples include thia-fatty acids,cyclopropenoid fatty acids, and certain conjugated linoleic acidisomers. Specifically, cis-12, trans-10 conjugated linoleic acid isbelieved to inhibit SCD enzyme activity and reduce the abundance of SCD1mRNA, while cis-9, trans-11 conjugated linoleic acid does not.Cyclopropenoid fatty acids, such as those found in stercula and cottonseeds, are also known to inhibit SCD activity. For example, sterculicacid (8-(2 octylcyclopropenyl)octanoic acid) and malvalic acid(7-(2-oclylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives ofsterculoyl and malvaloyl fatty acids, respectively, having cyclopropenerings at their C9-C10 position. These agents must be coupled to CoA toact as inhibitors, and are believed to inhibit SCD enzymatic activity bydirect interaction with the enzyme complex, thus inhibiting delta-9desaturation. Other agents that may inhibit SCD activity includethia-fatty acids, such as 9-thiastearic acid (also called8-nonylthiooctanoic acid) and other fatty acids.

There is a major unmet need for small molecule inhibitors of SCD enzymeactivity because compelling evidence now exists that SCD activity isdirectly implicated in common human disease processes: See e.g., Attie,A. D. et al, “Relationship between stearoyl-CoA desaturase activity andplasma triglycerides in human and mouse hypertriglyceridemia”, J. LipidRes. (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., “Role forstearoyl-CoA desaturase-1 in leptin mediated weight loss”, Science(2002), Vol. 297, No. 5579, pp. 240-3, Ntambi, J. M. et al., “Loss ofstearoyl-CoA desaturase-1 function protects mice against adiposity”,Proc. Natl. Acad. Sci. U.S.A. (2002), Vol. 99, No. 7, pp. 11482-6.

The present invention solves this problem by presenting new drug-likeclasses of compounds that are useful in modulating SCD activity andregulating lipid levels, especially plasma lipid levels, and which areuseful in the treatment of SCD-mediated diseases such as diseasesrelated to dyslipidemia and disorders of lipid metabolism, especiallydiseases related to elevated lipid levels, cardiovascular disease,diabetes, obesity, metabolic syndrome and the like.

SUMMARY OF THE INVENTION

The present invention provides heterocyclic derivatives that modulatethe activity of stearoyl-CoA desaturase. Methods of using suchderivatives to modulate the activity of stearoyl-CoA desaturase andpharmaceutical compositions comprising such derivatives are alsoencompassed.

Accordingly, in one aspect, the invention provides compounds of formula(I):

-   -   X is CH or N;    -   Y is NH, N—CH₃, O or S;    -   W is selected from —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—,        —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—, —S(O)_(t)—,        —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,        —OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)—, or a direct bond;    -   V is selected from —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—,        —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—, —S(O)_(t)—,        —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,        —OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond;    -   n is 0, 1, 2 or 3;    -   p is 0 to 9;    -   t is 1 or 2;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   or R¹ is a multi-ring structure having 2 to 4 rings wherein the        rings are independently selected from the group consisting of        cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or        all of the rings may be fused to each other;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   or R² is a multi-ring structure having 2 to 4 rings wherein the        rings are independently selected from the group consisting of        cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or        all of the rings may be fused to each other;    -   R³ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo,        haloalkyl, haloalkoxy, cyano and —N(R⁵)₂;    -   each R⁴ is independently selected from the group consisting of        alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,        alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;    -   or two R⁴s attached to the same carbon form an oxo while each of        the remaining R⁴s are as described above; each R⁵ is        independently selected from the group consisting of hydrogen,        alkyl, aryl, heteroaryl, cycloalkyl, hydroxyalkyl,        cycloalkylalkyl and aralkyl; and    -   R^(5a) is selected from the group consisting of hydrogen, alkyl,        cycloalkylalkyl and cyano; or    -   a stereoisomer, enantiomer or tautomer thereof, a        pharmaceutically acceptable salt thereof, a pharmaceutical        composition thereof or a prodrug thereof.

In another aspect, the invention provides methods of treating anSCD-mediated disease or condition in a mammal, preferably a human,wherein the methods comprise administering to the mammal in need thereofa therapeutically effective amount of a compound of the invention as setforth above.

In another aspect, the invention provides compounds or pharmaceuticalcompositions useful in treating, preventing and/or diagnosing a diseaseor condition relating to SCD biological activity such as the diseasesencompassed by cardiovascular disorders and/or metabolic syndrome(including dyslipidemia, insulin resistance and obesity).

In another aspect, the invention provides methods of preventing ortreating a disease or condition related to elevated lipid levels, suchas plasma lipid levels, especially elevated triglyceride or cholesterollevels, in a patient afflicted with such elevated levels, comprisingadministering to said patient a therapeutically or prophylacticallyeffective amount of a composition as disclosed herein. The presentinvention also relates to novel compounds having therapeutic ability toreduce lipid levels in an animal, especially triglyceride andcholesterol levels.

In another aspect, the invention provides pharmaceutical compositionscomprising the compounds of the invention as set forth above, andpharmaceutically acceptable excipients. In one embodiment, the presentinvention relates to a pharmaceutical composition comprising a compoundof the invention in a pharmaceutically acceptable carrier and in anamount effective to modulate triglyceride level, or to treat diseasesrelated to dyslipidemia and disorders of lipid metabolism, whenadministered to an animal, preferably a mammal, most preferably a humanpatient. In an embodiment of such composition, the patient has anelevated lipid level, such as elevated plasma triglycerides orcholesterol, before administration of said compound and said compound ispresent in an amount effective to reduce said lipid level.

In another aspect, the invention provides methods for treating a patientfor, or protecting a patient from developing, a disease or conditionmediated by stearoyl-CoA desaturase (SCD), which methods compriseadministering to a patient afflicted with such disease or condition, orat risk of developing such disease or condition, a therapeuticallyeffective amount of a compound that inhibits activity of SCD in apatient when administered thereto.

In another aspect, the invention provides methods for treating a rangeof diseases involving lipid metabolism and/or lipid homeostasisutilizing compounds identified by the methods disclosed herein. Inaccordance therewith, there is disclosed herein a range of compoundshaving said activity, based on a screening assay for identifying, from alibrary of test compounds, a therapeutic agent which modulates thebiological activity of said SCD and is useful in treating a humandisorder or condition relating to serum levels of lipids, such astriglycerides, VLDL, HDL, LDL, and/or total cholesterol.

It is understood that the scope of the invention as it relates tocompounds of formula (I) is not intended to encompass compounds whichare known, including, but not limited to, any specific compounds whichare disclosed and/or claimed in the following publications:

PCT Published Patent Application, WO 00/25768; PCT Published PatentApplication, WO 99/47507; PCT Published Patent Application, WO 01/60458;PCT Published Patent Application, WO 01/60369; PCT Published PatentApplication, WO 94/26720; European Published Patent Application, 0 438230; European Published Patent Application, 1 184 442;

CA 2,114,178; and U.S. Pat. No. 5,334,328;U.S. Pat. No. 5,310,499; and

US Published Patent Application, 2003/0127627. DETAILED DESCRIPTION OFTHE INVENTION Definitions

Certain chemical groups named herein are preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example, C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

Accordingly, as used in the specification and appended claims, unlessspecified to the contrary, the following terms have the meaningindicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl(t-butyl), and the like. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted by one or more of the following groups: alkyl, alkenyl,halo, haloalkyl, cyano, aryl, cycloalkyl, heterocyclyl, heteroaryl,—OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to2), —S(O)_(t)OR¹⁶, —SR¹⁶ (where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0to 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R¹⁶ is alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably two to eight carbon atoms or two to six carbon atoms andwhich is attached to the rest of the molecule by a single bond, e.g.,ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and thelike. Unless stated otherwise specifically in the specification, analkenyl group may be optionally substituted by one or more of thefollowing groups: alkyl, alkenyl, halo, haloalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —OR¹⁴—OC(O)—R¹⁴—N(R¹⁴)₂, —C(O)R¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶,—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 0 to2), —SR¹⁶, —S(O)_(t)R¹⁶ (where t is 1 to 2), and —S(O)_(t)N(R¹⁴)₂ (wheret is 1 to 2), where each R¹⁴ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R¹⁶ isalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms,preferably two to eight carbon atoms or two to six carbon atoms andwhich is attached to the rest of the molecule by a single bond. Unlessstated otherwise specifically in the specification, an alkynyl group maybe optionally substituted by one or more of the following groups: alkyl,alkenyl, halo, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR¹⁴,—OC(O)—R¹⁴—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 0 to 2), —SR¹⁶, —S(O)_(t)R¹⁶ (where t is 1 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalky; and eachR¹⁶ is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” refers to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen atoms, having from one totwelve carbon atoms, and linking the rest of the molecule to a radicalgroup, e.g., methylene, ethylene, propylene, n-butylene, and the like.The alkylene is attached to the rest of the molecule through a singlebond and to the radical group through a single bond. The points ofattachment of the alkeylene to the rest of the molecule and to theradical group can be through one carbon or any two carbons within thechain. Unless stated otherwise specifically in the specification, analkylene group may be optionally substituted by one or more of thefollowing groups: alkyl, alkenyl, halo, haloalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁴,—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 1 to2), —SR¹⁶, —S(O)_(t)R¹⁶ (where t is 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (wheret is 1 to 2), where each R¹⁴ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R¹⁶ isalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Alkenylene” refers to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to twelve carbon atoms, and linking therest of the molecule to a radical group, e.g. ethenylene, propenylene,n-butenylene, and the like. The alkenylene is attached to the rest ofthe molecule through a single bond and to the radical group through adouble bond or a single bond. The points of attachment of the alkeyleneto the rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkenylene group may be optionallysubstituted by one or more of the following groups: alkyl, alkenyl,halo, haloalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR¹⁴,—OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to2), —S(O)_(t)OR¹⁶ (where t is 1 to 2), —SR¹⁶, —S(O)_(t)R¹⁶ (where t is 1to 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.

“Alkynylene” refers to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen atoms, containing at least onetriple, having from two to twelve carbon atoms, and linking the rest ofthe molecule to a radical group, e.g. propynylene, n-butynylene, and thelike. The alkynylene is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. The pointsof attachment of the alkynylene to the rest of the molecule and to theradical group can be through one carbon or any two carbons within thechain. Unless stated otherwise specifically in the specification, analkynylene group may be optionally substituted by one or more of thefollowing groups: alkyl, alkenyl, halo, haloalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, N(R¹⁴)C(O)R¹⁶,—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 1 to2), —SR¹⁶, —S(O)_(t)R¹⁶ (where t is 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (wheret is 1 to 2), where each R¹⁴ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R¹⁶ isalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as generally defined above. The alkyl part of the alkoxyradical may be optionally substituted as defined above for an alkylradical.

“Alkoxyalkyl” refers to a radical of the formula —R_(a)—O—R₃ where eachR_(a) is independently an alkyl radical as defined above. The oxygenatom may be bonded to any carbon in either alkyl radical. Each alkylpart of the alkoxyalkyl radical may be optionally substituted as definedabove for an alkyl group.

“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ringsystem consisting only of hydrogen and carbon and containing from six tonineteen carbon atoms, preferably six to ten carbon atoms, where thering system may be partially saturated. Aryl groups include, but are notlimited to groups such as fluorenyl, phenyl and naphthyl. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano,nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (where tis 1 to 2), —R¹⁵—SR¹⁶, —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; each R¹⁵ is independently a direct bond or a straightor branched alkylene or alkenylene chain; and each R¹⁶ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above and R_(b) is one or more aryl radicalsas defined above, e.g., benzyl, diphenylmethyl and the like. The arylpart of the aralkyl radical may be optionally substituted as describedabove for an aryl group. The alkyl part of the aralkyl radical may beoptionally substituted as defined above for an alkyl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or bicyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having from three to fifteen carbon atoms, preferably having from threeto twelve carbon atoms or from three to seven atoms, and which issaturated or unsaturated and attached to the rest of the molecule by asingle bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decalinyl and the like. Unless otherwise stated specifically in thespecification, the term “cycloalkyl” is meant to include cycloalkylradicals which are optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, fluoro,haloalkyl, cyano, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)(S(O)R¹⁶) (where t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (where t is1 to 2), —R¹⁵—SR¹⁶, —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; each R¹⁵ is independently a direct bond or a straightor branched alkylene or alkenylene chain; and each R¹⁶ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The cycloalkyl part of the cycloalkylalkylradical may be optionally substituted as defined above for a cycloalkylradical. The alkyl part of the cycloalkylalkyl radical may be optionallysubstituted as defined above for an alkyl radical.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Haloalkoxy” refers to a radical of the formula —OR⁹ where R⁹ is ahaloalkyl group as defined above. The haloalkyl group may be optionallysubstituted as defined above for a haloalkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Forpurposes of this invention, the heterocyclyl radical may be amonocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems, which may be partially unsaturated; and thenitrogen, carbon or sulfur atoms in the heterocyclyl radical may beoptionally oxidized; the nitrogen atom may be optionallyalkylated/substituted; and the heterocyclyl radical may be partially orfully saturated. Examples of such heterocyclyl radicals include, but arenot limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl,homopiperidinyl, homopiperazinyl, and quinuclidinyl. Unless statedotherwise specifically in the specification, the term “heterocyclyl” ismeant to include heterocyclyl radicals as defined above which areoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, cyano, oxo, thioxo,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (where tis 1 to 2), —R¹⁵—SR¹⁶, —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; each R¹⁵ is independently a direct bond or a straightor branched alkylene or alkenylene chain; and each R¹⁶ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and where each of theabove substituents is unsubstituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkyl part of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkyl group. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heteroaryl” refers to a 5- to 18-membered aromatic ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic ortricyclic ring system, which may include fused or bridged ring systems,which may be partially saturated; and the nitrogen, carbon or sulfuratoms in the heteroaryl radical may be optionally oxidized; the nitrogenatom may be optionally alkylated/substituted. Examples include, but arenot limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl,benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl,benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl,benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,oxazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl. Unless stated otherwise specifically in thespecification, the term “heteroaryl” is meant to include heteroarylradicals as defined above which are optionally substituted by one ormore substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, cyano, oxo, thioxo, nitro, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂,—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)(S(O)_(t)R¹⁶) (where t is 1 to 2),—R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2), —R¹⁵—SR¹⁶, —R¹⁵—S(O)_(t)R¹⁶(where t is 0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2), whereeach R¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; each R¹⁵ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R¹⁶ isalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Hydroxyalkyl” refers to a radical of the formula —R_(a)—OH where R_(a)is an alkyl radical as defined above. The hydroxy group may be attachedto the alkyl radical on any carbon within the alkyl radical. The alkylpart of the hydroxyalkyl group may be optionally substituted as definedabove for an alkyl group.

“A multi-ring structure” refers to a multicyclic ring system comprisedof two to four rings wherein the rings are independently selected fromcycloalkyl, aryl, heterocyclyl or heteroaryl as defined above. Eachcycloalkyl may be optionally substituted as defined above for acycloalkyl group. Each aryl may be optionally substituted as definedabove for an aryl group. Each heterocyclyl may be optionally substitutedas defined above for a heterocyclyl group. Each heteroaryl may beoptionally substituted as defined above for a heteroaryl group. Therings may be attached to each other through direct bonds or some or allof the rings may be fused to each other.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood or conversion in the gut or liver. The prodrugcompound often offers advantages of solubility, tissue compatibility ordelayed release in a mammalian organism (see, Bundgard, H., Design ofProdrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AnglicanPharmaceutical Association arid Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto or acid group is bondedto any group that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto or acid group, respectively. Examples ofprodrugs include, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amides of amine functional groups in thecompounds of the invention and the like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphorirc acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients thereof.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of anSCD-mediated disease or condition in the mammal, preferably a human. Theamount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, and the age and body weight of themammal to be treated, but can be determined routinely by one of ordinaryskill in the art having regard to his own knowledge and to thisdisclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or disorder of interest, and includes: (i) preventing thedisease or condition from occurring in a mammal, in particular, whensuch mammal is predisposed to the condition but has not yet beendiagnosed as having it; (ii) inhibiting the disease or condition, i.e.,arresting its development; or (iii) relieving the disease or condition,i.e., causing regression of the disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

The chemical naming protocol and structure diagrams used herein employand rely on the chemical naming features as utilized by Chemdraw version10.0 (available from Cambridgesoft Corp., Cambridge, Mass.).

Embodiments of the Invention

One embodiment of the invention is the compounds of formula (I)

-   -   X is CH or N;    -   Y is NH, N—CH₃ O or S;    -   W is selected from —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—,        —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—, —S(O)_(t)—,        —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,        —OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)— or a direct bond;        -   V is selected from —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—,            —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—,            —S(O)_(t)—, —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—,            —OS(O)_(t)N(R⁵)—, —C(O)—, —OC(O)—, —C(O)O—,            —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,            —C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond;        -   n is 0, 1, 2 or 3;        -   p is 0 to 9;        -   t is 1 or 2;        -   R¹ is selected from the group consisting of hydrogen, alkyl,            alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, aryl, aralkyl, heterocyclyl,            heterocyclylalkyl, heteroaryl and heteroarylalkyl;        -   or R¹ is a multi-ring structure having 2 to 4 rings wherein            the rings are independently selected from the group            consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl            and where some or all of the rings may be fused to each            other;        -   R² is selected from the group consisting of hydrogen, alkyl,            alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, aryl, aralkyl, heterocyclyl,            heterocyclylalkyl, heteroaryl and heteroarylalkyl;        -   or R² is a multi-ring structure having 2 to 4 rings wherein            the rings are independently selected from the group            consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl            and where some or all of the rings may be fused to each            other;        -   R³ is selected from the group consisting of hydrogen, alkyl,            alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,            halo, haloalkyl, haloalkyoxy, cyano and —N(R⁵)₂;        -   each R⁴ is independently selected from the group consisting            of alkyl, halo, haloalkyl, haloalkoxy, hydroxyl,            hydroxyalkyl, alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;        -   or two R⁴s attached to the same carbon form an oxo while            each of the remaining R⁴s are as described above;        -   R⁵ is selected from the group consisting of hydrogen, alkyl,            aryl, heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl            and aralkyl; and        -   R^(5a) is selected from the group consisting of hydrogen,            alkyl, cycloalkylalkyl and cyano; or        -   a stereoisomer, enantiomer or tautomer thereof, a            pharmaceutically acceptable salt thereof, a pharmaceutical            composition thereof or a prodrug thereof.

A more preferred embodiment of formula (I), wherein

-   -   V is ═C(R⁵)—, —N(R⁵)₂— or a direct bond;    -   W is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —C(O)O— or a direct bond;    -   X is N or CH;    -   Y is S;    -   p is 1, 2, 3, 4, 5, 6 or 7;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl and heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,        aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and        heteroarylalkyl;    -   R³ is hydrogen or alkyl; and    -   R⁵ is hydrogen or alkyl.

A more preferred embodiment of Formula I, wherein

-   -   V is a direct bond;    -   W is —N(R⁵)C(O)— or —C(O)O—;    -   X is N or CH;    -   Y is S;    -   p is 1, 2, 3, 4, 5, 6 or 7;    -   R¹ is selected from the group consisting of alkyl, aryl,        aralkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl and        heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl and        aralkyl;    -   R³ is hydrogen or alkyl; and    -   R⁵ is hydrogen or alkyl.

A more preferred embodiment of Formula I, wherein

-   -   V is a direct bond;    -   W is —N(R⁵)C(O)—;    -   X is N or CH;    -   Y is S;    -   p is 1, 2, 3, 4, 5, 6 or 7;    -   n is 1 or 2;    -   R¹ is selected from the group consisting of alkyl, aryl, aralkyl        and heteroaryl;    -   R² is selected from the group consisting of alkyl, hydroxyalkyl,        alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl;    -   R³ is alkyl; and    -   R⁵ is hydrogen.

Another preferred embodiment of the invention relates to a compound offormula (I) wherein n is 1, X is N and Y is S, i.e., compound having thefollowing formula (Ia):

where p, W, V, R¹, R², R³ and R⁴ are as defined above in the Summary ofthe Invention.

Of this group of compounds, a subgroup of compounds are those compoundswherein:

-   -   W is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—, —N(R⁵)C(O)O—,        —N(R⁵)C(O)N(R⁵)—, —O—, —S, —N(R⁵)—, —S(O)_(t)—, —N(R⁵)S(O)_(t)—,        —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—, —OC(O)—, —C(O)O—,        —N(R⁵)C(═N(R^(5a)))NR⁵, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)— or a direct bond;    -   V is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—, —N(R⁵)C(O)O—,        —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—, —S(O)_(t)—,        —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,        —OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond;    -   p is 0 to 5;    -   t is 1 or 2;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R³ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo,        haloalkyl, haloalkyoxy, cyano and —N(R⁵)₂;    -   each R⁴ is independently selected from the group consisting of        alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,        alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;    -   or two R⁴s attached to the same carbon form an oxo while each of        the remaining R⁴s are as described above;    -   each R⁵ is independently selected from the group consisting of        hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, hydroxyalkyl,        cycloalkylalkyl and aralkyl; and    -   R^(5a) is selected from the group consisting of hydrogen, alkyl,        cycloalkylalkyl, and cyano.

Of this subgroup, a set of compounds are those compounds wherein:

-   -   W is —N(R⁵)C(O)— or —N(R⁵)S(O)_(t)—;    -   V is a direct bond or —N(R⁵)—;    -   p is 0, 1, 2, 3, 4 or 5;    -   t is 1 or 2;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R³ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo,        haloalkyl, haloalkyoxy, cyano and —N(R⁵)₂;    -   each R⁴ is independently selected from the group consisting of        alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,        alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;    -   or two R⁴s attached to the same carbon form an oxo while each of        the remaining R⁴s are as described above; and    -   each R⁵ is independently selected from the group consisting of        hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, hydroxyalkyl,        cycloalkylalkyl and aralkyl; Of this set of compounds, a subset        of compounds are those compounds wherein:    -   W is —N(H)C(O)—;    -   V is a direct bond or —N(H)—;    -   p is 0, 1, 2, 3, 4 or 5;    -   R¹ is aralkyl or heteroarylalkyl;    -   R² is hydrogen, cycloalkylalkyl, aryl, aralkyl, heteroaryl or        heteroarylalkyl;    -   R³ is hydrogen or alkyl; and    -   each R⁴ is independently alkyl, hydroxyl or halo.

A further preferred embodiment of the invention relates to a compound offormula (I) wherein n is 2, X is N and Y is S, i.e., compound having thefollowing formula (Ib):

where p, W, V, R¹, R², R³ and R⁴ are as defined above in the Summary ofthe Invention.

Of this group of compounds, a subgroup of compounds are those compoundswherein:

-   -   W is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—, —N(R⁵)C(O)O—,        —N(R⁵)C(O)N(R⁵)—, —O—, —S, —N(R⁵)—, —S(O)_(t)—, —N(R⁵)S(O)_(t)—,        —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—, —OC(O)—, —C(O)O—,        —N(R⁵)C(═N(R^(5a)))NR⁵, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)— or a direct bond;    -   V is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)N(R⁵)—, —N(R⁵)C(O)O—,        —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—, —S(O)_(t)—,        —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,        —OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵, —N(R⁵)((R^(5a))N═)C—,        —C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond;    -   p is 0, 1, 2, 3, 4, 5, 6 or 7;    -   t is 1 or 2;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R³ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo,        haloalkyl, haloalkoxy, cyano and —N(R⁵)₂;    -   each R⁴ is independently selected from the group consisting of        alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,        alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        aryl, heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, and        aralkyl; and    -   R^(5a) is selected from the group consisting of hydrogen, alkyl,        cycloalkylalkyl, and cyano.

Of this subgroup, a set of compounds are those compounds wherein:

-   -   W is —N(R⁵)C(O)— or —N(R⁵)S(O)_(t)—;    -   V is a direct bond, —N(R⁵)— or ═C(R⁵)—;    -   p is 0, 1, 2, 3, 4, 5, 6 or 7;    -   t is 1 or 2;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R² is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl and heteroarylalkyl;    -   R³ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo,        haloalkyl, haloalkoxy, cyano, and —N(R⁵)₂;    -   each R⁴ is independently selected from the group consisting of        alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,        alkoxy, —N(R⁵)₂, cycloalkylalkyl and aralkyl;    -   or two R⁴s attached to the same carbon form an oxo while each of        the remaining R⁴s are as described above; and    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        aryl, heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl and        aralkyl.

Of this set of compounds, a subset of compounds are those compoundswherein:

-   -   W is —N(H)C(O)—;    -   V is a direct bond, —N(H)— or ═C(H)—;    -   p is 0, 1, 2, 3, 4 or 5;    -   R¹ is aralkyl or heteroarylalkyl;    -   R² is hydrogen, cycloalkylalkyl, aryl, aralkyl, heteroaryl or        heteroarylalkyl;    -   R³ is hydrogen or alkyl; and    -   each R⁴ is independently alkyl, hydroxyl, oxo or halo;    -   or two R⁴s attached to the same carbon form an oxo while each of        the remaining R⁴s are as described above.

In one embodiment, the methods of the invention are directed towards thetreatment and/or prevention of diseases mediated by stearoyl-CoAdesaturase (SCD), especially human SCD (hSCD), preferably diseasesrelated to dyslipidemia and disorders of lipid metabolism, andespecially a disease related to elevated plasma lipid levels,cardiovascular disease, diabetes, obesity, metabolic syndrome,dermatological disorders and the like by administering an effectiveamount of a compound of the invention.

The present invention also relates to pharmaceutical compositioncontaining the compounds of the invention. In one embodiment, theinvention relates to a composition comprising compounds of the inventionin a pharmaceutically acceptable carrier and in an amount effective tomodulate triglyceride level or to treat diseases related to dyslipidemiaand disorders of lipid metabolism, when administered to an animal,preferably a mammal, most preferably a human patient. In an embodimentof such composition, the patient has an elevated lipid level, such aselevated triglycerides or cholesterol, before administration of saidcompound of the invention and the compound of the invention is presentin an amount effective to reduce said lipid level.

Utility and Testing of the Compounds Of The Invention

The present invention relates to compounds, pharmaceutical compositionsand methods of using the compounds and pharmaceutical compositions forthe treatment and/or prevention of diseases mediated by stearoyl-CoAdesaturase (SCD), especially human SCD (hSCD), preferably diseasesrelated to dyslipidemia and disorders of lipid metabolism, andespecially a disease related to elevated plasma lipid levels, especiallycardiovascular disease, diabetes, obesity, metabolic syndrome,dermatological disorders and the like, by administering to a patient inneed of such treatment an effective amount of an SCD modulating,especially inhibiting, agent.

In general, the present invention provides a method for treating apatient for, or protecting a patient from developing, a disease relatedto dyslipidemia and/or a disorder of lipid metabolism, wherein lipidlevels in an animal, especially a human being, are outside the normalrange (i.e., abnormal lipid level, such as elevated plasma lipidlevels), especially levels higher than normal, preferably where saidlipid is a fatty acid, such as a free or complexed fatty acid,triglycerides, phospholipids, or cholesterol, such as whereLDL-cholesterol levels are elevated or HDL-cholesterol levels arereduced, or any combination of these, where said lipid-related conditionor disease is an SCD-mediated disease or condition, comprisingadministering to an animal, such as a mammal, especially a humanpatient, a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a compound of theinvention wherein the compound modulates the activity of SCD, preferablyhuman SCD1.

The compounds of the invention modulate, preferably inhibit, theactivity of human SCD enzymes, especially human SCD1.

The general value of the compounds of the invention in modulating,especially inhibiting, the activity of SCD can be determined using theassay described below in Example 12.

Alternatively, the general value of the compounds in treating disordersand diseases may be established in industry standard animal models fordemonstrating the efficacy of compounds in treating obesity, diabetes orelevated triglyceride or cholesterol levels or for improving glucosetolerance. Such models include Zucker obese fa/fa rats (available fromHarlan Sprague Dawley, Inc. (Indianapolis, Ind.)), or the Zuckerdiabetic fatty rat (ZDF/GmiCrl-fa/fa) (available from Charles RiverLaboratories (Montreal, Quebec)), and Sprague Dawley rats (CharlesRivers), as used in models for diet-induced obesity (Ghibaudi, L. et al,(2002), Obes. Res. Vol. 10, pp. 956-963). Similar models have also beendeveloped for mice and Lewis rat.

The compounds of the instant invention are inhibitors of delta-9desaturases and are useful for treating diseases and disorders in humansand other organisms, including all those human diseases and disorderswhich are the result of aberrant delta-9 desaturase biological activityor which may be ameliorated by modulation of delta-9 desaturasebiological activity.

As defined herein, an SCD-mediated disease or condition is defined asany disease or condition in which the activity of SCD is elevated and/orwhere inhibition of SCD activity can be demonstrated to bring aboutsymptomatic improvements for the individual so treated. As definedherein, an SCD-mediated disease or condition includes, but is notlimited to, a disease or condition which is, or is related to,cardiovascular disease, dyslipidemias (including but not limited todisorders of serum levels of triglycerides, hypertriglyceridemia, VLDL,HDL, LDL, fatty acid Desaturation Index (e.g. the ratio of 18:1/18:0fatty acids, or other fatty acids, as defined elsewhere herein),cholesterol, and total cholesterol, hypercholesterolemia, as well ascholesterol disorders (including disorders characterized by defectivereverse cholesterol transport)), familial combined hyperlipidemia,coronary artery disease, atherosclerosis, heart disease, cerebrovasculardisease (including but not limited to stroke, ischemic stroke andtransient ischemic attack (TIA)), peripheral vascular disease, andischemic retinopathy.

An SCD-mediated disease or condition also includes metabolic syndrome(including but not limited to dyslipidemia, obesity and insulinresistance, hypertension, microalbuminemia, hyperuricaemia, andhypercoagulability), Syndrome X, diabetes, insulin resistance, decreasedglucose tolerance, non-insulin-dependent diabetes mellitus, Type IIdiabetes, Type I diabetes, diabetic complications, body weight disorders(including but not limited to obesity, overweight, cachexia andanorexia), weight loss, body mass index and leptin-related diseases. Ina preferred embodiment, compounds of the invention will be used to treatdiabetes mellitus and/or obesity.

As used herein, the term “metabolic syndrome” is a recognized clinicalterm used to describe a condition comprising combinations of Type IIdiabetes, impaired glucose tolerance, insulin resistance, hypertension,obesity, increased abdominal girth, hypertriglyceridemia, low HDL,hyperuricaernia, hypercoagulability and/or microalbuminemia. TheAmerican Heart Association has published guidelines for the diagnosis ofmetabolic syndrome, Grundy, S., et. al., (2006) Cardiol. Rev. Vol. 13,No. 6, pp. 322-327.

An SCD-mediated disease or condition also includes fatty liver, hepaticsteatosis, hepatitis, non-alcoholic hepatitis, non-alcoholicsteatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fattyliver of pregnancy, drug-induced hepatitis, erythrohepaticprotoporphyria, iron overload disorders, hereditary hemochromatosis,hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions relatedthereto.

An SCD-mediated disease or condition also includes but is not limited toa disease or condition which is, or is related to primaryhypertriglyceridemia, or hypertriglyceridemia secondary to anotherdisorder or disease, such as hyperlipoproteinemias, familial histiocyticreticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency(such as ApoCII deficiency or ApoE deficiency), and the like, orhypertriglyceridemia of unknown or unspecified etiology.

An SCD-mediated disease or condition also includes a disorder ofpolyunsaturated fatty acid (PUFA) disorder, or a skin disorder,including but not limited to eczema, acne, psoriasis, keloid scarformation or prevention, diseases related to production or secretionsfrom mucous membranes, such as monounsaturated fatty acids, wax esters,and the like. Preferably, the compounds of the invention will prevent orattenuate keloid scar formation by reduction of excessive sebumproduction that typically results in their formation. The investigationof the role of SCD inhibitors in the treatment of acne was advanced bythe discovery that rodents lacking a functional SCD1 gene had changes tothe condition of their eyes, skin, coat (Zheng Y., et al. “SCD1 isexpressed in sebaceous glands and is disrupted in the asebia mouse”,Nat. Genet. (1999) 23:268-270. Miyazaki, M., “Targeted Disruption ofStearoyl-CoA Desaturasel Gene in Mice Causes Atrophy of Sebaceous andMeibomian Glands and Depletion of Wax Esters in the Eyelid”, J. Nutr.(2001), Vol. 131, pp 2260-68., Binczek, E. et al., “Obesity resistanceof the stearoyl-CoA desaturase-deficient mouse results from disruptionof the epidermal lipid barrier and adaptive thermoregulation”, Biol.Chem. (2007) Vol. 388 No. 4, pp 405-18).

An SCD-mediated disease or condition also includes inflammation,sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis,cystic fibrosis, and premenstrual syndrome.

An SCD-mediated disease or condition also includes but is not limited toa disease or condition which is, or is related to cancer, neoplasia,malignancy, metastases, tumours (benign or malignant), carcinogenesis,hepatomas and the like.

An SCD-mediated disease or condition also includes a condition whereincreasing lean body mass or lean muscle mass is desired, such as isdesirable in enhancing performance through muscle building. Myopathiesand lipid myopathies such as carnitine palmitoyltransferase deficiency(CPT I or CPT II) are also included herein. Such treatments are usefulin humans and in animal husbandry, including for administration tobovine, porcine or avian domestic animals or any other animal to reducetriglyceride production and/or provide leaner meat products and/orhealthier animals.

An SCD-mediated disease or condition also includes a disease orcondition that is, or is related to, psychiatric disorders, multiplesclerosis, eye diseases, and immune disorders.

An SCD-mediated disease or condition also includes neurologicaldiseases, including mild cognitive impairment, depression,schizophrenia, obsessive-compulsive disorder, and biopolar disorder.

An SCD-mediated disease or condition also includes neurodegenerativediseases, including Alzheimer's disease, Parkinson's disease, dementiawith Lewy bodies, amyotrophic lateral sclerosis or Lou Gehrig's disease,Alpers' disease, Leigh's disease, Pelizaeus-Merzbacher disease,Olivopontocerebellar atrophy, Friedreich's ataxia, leukodystrophies,Rett syndrome, Ramsay Hunt syndrome type II, and Down's syndrome.

An SCD-mediated disease or condition also includes a disease orcondition which is, or is related to, viral diseases or infectionsincluding but not limited to all positive strand RNA viruses,coronaviruses, SARS virus, SARS-associated coronavirus, Togaviruses,Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae,ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equineencephalitis virus, Western equine encephalitis virus, Venezuelan equineencephalitis virus, Sindbis virus, Semliki forest virus, Chikungunyavirus, O'nyong'nyong virus, Ross river virus, Mayaro virus,Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses;CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalkvirus, Calicivirus, Bovine calicivirus, Pig calcivirus, Hepatitis E;CORONAVIRIDAE including Coronavirus, SARS virus, Avian infectiousbronchitis virus, Bovine coronavirus, Canine coronavirus, Felineinfectious peritonitis virus, Human coronavirus 299E, Human coronavirusOC43, Murine hepatitis virus, Porcine epidemic diarrhea virus, Porcinehemagglutinating encephalomyelitis virus, Porcine transmissiblegastroenteritis virus, Rat coronavirus, Turkey coronavirus, Rabbitcoronavirus, Berne virus, Breda virus; FLAVIVIRIDAE including HepatitisC virus, West Nile virus, Yellow Fever virus, St. Louis encephalitisvirus, Dengue Group, Hepatitis G virus, Japanese B encephalitis virus,Murray Valley encephalitis virus, Central European tick-borneencephalitis virus, Far Eastern tick-borne encephalitis virus, Kyasanurforest virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fevervirus, Kumilinge virus, Absetarov anzalova hypr virus, lTheus virus,Rocio encephalitis virus, Langat virus, Pestivirus, Bovine viraldiarrhea, Hog cholera virus, Rio Bravo Group, Tyuleniy Group, NtayaGroup, Uganda S Group, Modoc Group; PICORNAVIRIDAE including Coxsackie Avirus, Rhinovirus, Hepatitis A virus, Encephalomyocarditis virus,Mengovirus, ME virus, Human poliovirus 1, Coxsackie B; POCYVIRIDAEincluding Potyvirus, Rymovirus, Bymovirus. Additionally it can be adisease or infection caused by or linked to Hepatitis viruses, HepatitisB virus, Hepatitis C virus, human immunodeficiency virus (HIV) and thelike. Treatable viral infections include those where the virus employsan RNA intermediate as part of the replicative cycle (hepatitis or HIV);additionally it can be a disease or infection caused by or linked to RNAnegative strand viruses such as influenza and parainfluenza viruses.

The compounds identified in the instant specification inhibit thedesaturation of various fatty acids (such as the C₉-C₁₀ desaturation ofstearoyl-CoA), which is accomplished by delta-9 desaturases, such asstearoyl-CoA desaturase 1 (SCD1). As such, these compounds inhibit theformation of various fatty acids and downstream metabolites thereof.This may lead to an accumulation of stearoyl-CoA or palmitoyl-CoA andother upstream precursors of various fatty acids; which may possiblyresult in a negative feedback loop causing an overall change in fattyacid metabolism. Any of these consequences may ultimately be responsiblefor the overall therapeutic benefit provided by these compounds.

Typically, a successful SCD inhibitory therapeutic agent will meet someor all of the following criteria. Oral availability should be at orabove 20%. Animal model efficacy is less than about 10 mg/Kg, 2 mg/Kg, 1mg/Kg, or 0.5 mg/Kg and the target human dose is between 10 and 250mg/70 Kg, although doses outside of this range may be acceptable.(“mg/Kg” means milligrams of compound per kilogram of body mass of thesubject to whom it is being administered). The required dosage shouldpreferably be no more than about once or twice a day or at meal times.The therapeutic index (or ratio of toxic dose to therapeutic dose)should be greater than 10. The IC₅₀ (“Inhibitory Concentration—50%”) isa measure of the amount of compound required to achieve 50% inhibitionof SCD activity, over a specific time period, in an SCD biologicalactivity assay. Any process for measuring the activity of SCD enzymes,preferably mouse or human SCD enzymes, may be utilized to assay theactivity of the compounds useful in the methods of the invention ininhibiting said SCD activity. Compounds of the invention demonstrate anIC₅₀ (“Inhibitory Concentration of 50%”) in a 15 minute microsomal assayof preferably less than 10 μM, less than 5 μM, less than 2.5 μM, lessthan 1 μM, less than 750 nM, less than 500 nM, less than 250 nM, lessthan 100 nM, less than 50 nM, and most preferably less than 20 nM.Compounds of the invention may show reversible inhibition (i.e.,competitive inhibition) and preferably do not inhibit other iron bindingproteins.

The identification of compounds of the invention as SCD inhibitors wasreadily accomplished using the SCD enzyme and microsomal assay proceduredescribed in Shanklin J. and Summerville C., Proc. Natl. Acad. Sci. USA(1991), Vol. 88, pp. 2510-2514. When tested in this assay, compounds ofthe invention had less than 50% remaining SCD activity at 10 μMconcentration of the test compound, preferably less than 40% remainingSCD activity at 10 μM concentration of the test compound, morepreferably less than 30% remaining SCD activity at 10 μM concentrationof the test compound, and even more preferably less than 20% remainingSCD activity at 10 μM concentration of the test compound, therebydemonstrating that the compounds of the invention are potent inhibitorsof SCD activity.

These results provide the basis for analysis of the structure-activityrelationship (SAR) between test compounds and SCD. Certain-groups tendto provide more potent inhibitory compounds. SAR analysis is one of thetools those skilled in the art may employ to identify preferredembodiments of the compounds of the invention for use as therapeuticagents. Other methods of testing the compounds disclosed herein are alsoreadily available to those skilled in the art. Thus, in addition, thedetermination of the ability of a compound to inhibit SCD may beaccomplished in vivo. In one such embodiment this is accomplished byadministering said chemical agent to an animal afflicted with atriglyceride (TG)- or very low density lipoprotein (VLDL)-relateddisorder and subsequently detecting a change in plasma triglyceridelevel in said animal thereby identifying a therapeutic agent useful intreating a triglyceride (-TG)- or very low density lipoprotein(VLDL)-related disorder. In such embodiment, the animal may be a human,such as a human patient afflicted with such a disorder and in need oftreatment of said disorder.

In specific embodiments of such in vivo processes, said change in SCD1activity in said animal is a decrease in activity, preferably whereinsaid SCD1 modulating agent does not substantially inhibit the biologicalactivity of a delta-5 desaturase, delta-6 desaturase or fatty acidsynthetase or other enzymes containing iron at the active site.

The model systems useful for compound evaluation may include, but arenot limited to, the use of liver microsomes, such as from mice that havebeen maintained on a high carbohydrate diet, or from human donors,including persons suffering from obesity. Immortalized cell lines, suchas HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1(from mouse adipocytes) may also be used. Primary cell lines, such asmouse primary hepatocytes, are also useful in testing the compounds ofthe invention. Where whole animals are used, mice used as a source ofprimary hepatocyte cells may also be used wherein the mice have beenmaintained on a high carbohydrate diet to increase SCD activity inmirocrosomes and/or to elevate plasma triglyceride levels (i.e., the18:1/18:0 ratio); alternatively mice on a normal diet or mice withnormal triglyceride levels may be used. Mouse models employingtransgenic mice designed for hypertriglyceridemia are also available.Rabbits and hamsters are also useful as animal models, especially thoseexpressing CETP (cholesterol ester transfer protein).

Another suitable method for determining the in vivo efficacy of thecompounds of the invention is to indirectly measure their impact oninhibition of SCD enzyme by measuring a subject's Desaturation Indexafter administration of the compound.

“Desaturation Index” as employed in this specification means the ratioof the product over the substrate for the SCD enzyme as measured from agiven tissue sample. This may be calculated using three differentequations 18:1n-9/18:0 (oleic acid over stearic acid); 16:1n-7/16:0(palmitoleic acid over palmitic acid); and/or 16:1n-7+18:1n-7/16:0(measuring all reaction products of 16:0 desaturation over 16:0substrate).

Desaturation Index is primarily measured in liver or plasmatriglycerides, but may also be measured in other selected lipidfractions from a variety of tissues. Desaturation Index, generallyspeaking, is a tool for plasma lipid profiling.

A number of human diseases and disorders are the result of aberrant SCD1biological activity and may be ameliorated by modulation of SCD1biological activity using the therapeutic agents of the invention.

Inhibition of SCD expression may also affect the fatty acid compositionof membrane phospholipids, as well as production or levels oftriglycerides and cholesterol esters. The fatty acid composition ofphospholipids ultimately determines membrane fluidity, with a subsequentmodulation of the activity of multiple enzymes present within themembrane, while the effects on the composition of triglycerides andcholesterol esters can affect lipoprotein metabolism and adiposity.

In carrying out the procedures of the present invention it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented.

For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

Alternatively, another format can be used to measure the effect of SCDinhibition on sebaceous gland function. In a typical study usingridnets, oral, intravenous or topical formulations of the SCD inhibitorare administered to a rodent for a period of 1 to 8 days. Skin samplesare taken and prepared for histological assessment to determinesebaceous gland number, size, or lipid content. A reduction of sebaceousgland size, number or function would indicate that the SCD inhibitorwould have a beneficial impact on acne vulgaris, (Clark, S. B. et al.“Pharmacological modulation of sebaceous gland activity: mechanisms andclinical applications”, Dermatol. Clin. (2007) Vol. 25, No. 2, pp137-46. Geiger, J. M., “Retinoids and sebaceous gland activity”Dermatology (1995), Vol. 191, No. 4, pp 305-10).

Pharmaceutical Compositions of the Invention and Administration

The present invention also relates to pharmaceutical compositioncontaining the compounds of the invention disclosed herein. In oneembodiment, the present invention relates to a composition comprisingcompounds of the invention in a pharmaceutically acceptable carrier andin an amount effective to modulate triglyceride level or to treatdiseases related to dyslipidemia and disorders of lipid metabolism, whenadministered to an animal, preferably a mammal, most preferably a humanpatient. In an embodiment of such composition, the patient has anelevated lipid level, such as elevated triglycerides or cholesterol,before administration of said compound of the invention and the compoundof the invention is present in an amount effective to reduce said lipidlevel.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES(Mack Pub. Co., N.J. current edition).

Those skilled in the art are familiar with how to determine suitabledoses of the compounds for use in treating the diseases and disorderscontemplated herein.

Therapeutic doses are generally identified through a dose ranging studyin humans based on preliminary evidence derived from animal studies.Doses must be sufficient to result in a desired therapeutic benefitwithout causing unwanted side effects for the patient. The preferreddosage range for an animal is 0.001 mg/Kg to 10,000 mg/Kg, including 0.5mg/Kg, 1.0 mg/Kg, 2.0 mg/Kg 5.0 mg/Kg and 10 mg/Kg, though doses outsidethis range may be acceptable. The dosing schedule may be once or twiceper day, although more often or less often may be satisfactory.

Those skilled in the art are also familiar with determiningadministration methods (oral, intravenous, inhalation, sub-cutaneous,transdermal (topical), etc.), dosage forms, suitable pharmaceuticalexcipients and other matters relevant to the delivery of the compoundsto a subject in need thereof.

In an alternative use of the invention, the compounds of the inventioncan be used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to inhibit stearoyl-CoAdesaturase, and for the treatment of conditions associated with stearoyldesaturase activity. In general, the pharmaceutical compositionscomprise a therapeutically effective amount of a pharmacologicallyactive compound of the instant invention, alone or in combination withone or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising atherapeutically effective amount thereof in conjunction or admixturewith excipients or carriers suitable for either enteral or parenteralapplication. For enteral or parenteral application, it is preferred toadminister an effective amount of a pharmaceutical composition accordingto the invention as tablets or gelatin capsules. Such pharmaceuticalcompositions may comprise, for example, the active ingredient togetherwith diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine), lubricants (e.g., silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol), and fortablets also comprises binders (e.g., magnesium aluminum silicate,starch paste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone) and disintegrants(e.g., starches, agar, alginic acid or its sodium salt) or effervescentmixtures and absorbants, colorants, flavors and sweeteners.

In another aspect of the present invention the compounds may be in theform of injectable compositions, e.g. preferably aqueous isotonicsolutions or suspensions, and suppositories, which can be advantageouslyprepared from fatty emulsions or suspensions. The compositions may besterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. In addition, they may also containother therapeutically valuable substances. The compositions may beprepared according to conventional mixing, granulating or coatingmethods, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate-controlling barrier todeliver the compound of the skin of the host at a controlled andpre-determined rate over a prolonged period of time, and means to securethe device to the skin.

The most suitable route will depend on the nature and severity of thecondition being treated. Those skilled in the art are also familiar withdetermining administration methods, dosage forms, suitablepharmaceutical excipients and other matters relevant to the delivery ofthe compounds to a subject in need thereof.

The compounds of the invention may be usefully combined with one or moreother therapeutic agents for the treatment of SCD-mediated diseases andconditions. Preferrably, the other therapeutic agent is selected fromantidiabetics, hypolipidemic agents, anti-obesity agents,anti-hypertensive agents or inotropic agents.

Thus, an additional aspect of the present invention concerns apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention in combination with one or more othertherapeutic agents. For example, the composition can be formulated tocomprise a therapeutically effective amount of a compound of theinvention as defined above, in combination with another therapeuticagent, each at an effective therapeutic dose as reported in the art.Such therapeutic agents may, for example, include insulin, insulinderivatives and mimetics; insulin secretagogues, such as thesulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropicsulfonylurea receptor ligands, such as meglitinides, e.g., nateglinideand repaglinide; PPARγ and/or PPARα (peroxisome proliferator-activatedreceptor) ligands such as MCC-555, MK767, L-165041, GW7282 orthiazolidinediones such as rosiglitazone, pioglitazone, troglitazone;insulin sensitizers, such as protein tyrosine phosphatase-1B (PTP-1B)inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitorssuch as SB-517955, SB-4195052, SB-216763, N,N-57-05441, N,N-57-05445 orRXR ligands such as GW-0791, AGN-194204; sodium-dependent glucosecotransporter inhibitors, such as T-1095, glycogen phosphorylase Ainhibitors, such as BAY R3401; biguanides, such as metformin;alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon likepeptide-1), GLP-1 analogs, such as Exendin-4, and GLP-1 mimetics; DPPIV(dipeptidyl peptidase IV) inhibitors such as LAF237 (Vildagliptin);hypolipidemic agents, such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin,simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,fluvastatin, dalvastatin, atorvastatin, rosuvastatin, fluindostatin andrivastatin, squalene synthase inhibitors or FXR (farnesoid X receptor)and LXR (liver X receptor) ligands, cholestyramine, fibrates, nicotinicacid and aspirin; anti-obesity agents, such as orlistat,anti-hypertensive agents, inotropic agents and hypolipidemic agents,e.g., loop diuretics, such as ethacrynic acid, furosemide and torsemide;angiotensin converting enzyme (ACE) inhibitors, such as benazepril,captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril,quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPasemembrane pump, such as digoxin; neutralendopeptidase (NEP) inhibitors;ACE/NEP inhibitors, such as omapatrilat, sampatrilat and fasidotril;angiotensin II antagonists, such as candesartan, eprosartan, irbesartan,losartan, telmisartan and valsartan, in particular valsartan;β-adrenergic receptor blockers, such as acebutolol, atenolol, betaxolol,bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol;inotropic agents, such as digoxin, dobutamine and milrinone; calciumchannel blockers, such as amlodipine, bepridil, diltiazem, felodipine,nicardipine, nimodipine, nifedipine, nisoldipine and verapamil. Otherspecific antidiabetic compounds are described by Patel Mona (Expert OpinInvestig Drugs. (2003) April; 12(4):623-33) in the FIGS. 1 to 7, whichare herein incorporated by reference. A compound of the presentinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The structure of the active agents identified by code numbers (nos.),generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

In another aspect is the use of the pharmaceutical composition asdescribed above for production of a medicament for the treatment ofSCD-mediated disease or conditions.

In another aspect is the use of a pharmaceutical composition orcombination as described above for the preparation of a medicament forthe treatment of conditions associated with stearoyl-CoA desatruaseactivity.

A pharmaceutical composition as described above for the treatment ofconditions associated with the inhibition of stearoyl-CoA desaturase.

Preparations of Compounds

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (2006),4th Ed., Wiley. The protecting group may also be a polymer resin such asa Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following reaction schemes illustrate methods to make compounds ofthis invention. It is understood that one skilled in the art would beable to make these compounds by similar methods or by methods known toone skilled in the art. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,5th edition (Wiley, December 2000)) or prepared as described in thisinvention. R¹, R², R³, R⁴, R⁵, X, Y, W and V are defined as in theSpecification unless specifically defined. R′ is a protecting group.

In general, the compounds of Formula (I) of this invention can besynthesized following the general procedure as described in ReactionScheme 1, where W is —N(R⁵)C(O)—.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction scheme as follows:

The coupling of the amino carboxylic acid (101) and amine compound (102)under standard amide bond formation conditions known to the one skilledin the art affords compound (103). Compound (103) undergoes anotheramide bond formation reaction with acid (104) to generate compound (105)which undergoes intramolecular cyclization in the presence of a base,such as, but not limited to, potassium carbonate to afford the cyclizedcompound (106). Compound (106) is used as a key intermediate to generatecompounds of Formula (I) under the conditions of (a) alkylation, or (b)aldol condensation followed by hydrogenation, or (c) bromination togenerate compound (107), followed by amine displacement.

Alternatively, the compounds of Formula (I) of this invention can besynthesized following the general procedure as described in ReactionScheme 2, where W is —N(R⁵)C(O)—.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction scheme as follows:

The starting compound (201) undergoes coupling reaction with amine (102)under standard amide bond formation conditions known to the one skilledin the art to afford compound (203). Compound (203) is then coupled withcompound (204) under metal catalyzed reaction conditions to generatecompound of Formula (I), where W is —N(R⁵)C(O)—.

Alternatively, the compounds of Formula (I) of this invention can besynthesized following the general procedure as described in ReactionScheme 3 where W is —N(R⁵)C(O)—.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction scheme as follows:

The starting amino compound (103) reacts with compound (301) in thepresence of a base, such as, but not limited to, triethylamine, toafford compound of Formula (I).

Although one skilled in the art is capable of preparing the compounds ofthe invention according to the general techniques disclosed above, morespecific details on synthetic techniques for compounds of the inventionare provided elsewhere in this specification for convenience. Again, allreagents and reaction conditions employed in synthesis are known tothose skilled in the art and are available from ordinary commercialsources.

Preparation 1 Preparation of2-amino-N-benzyl-4-methylthiazole-5-carboxamide

A. A mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (6.58 g,35.5 mmol) and NaOH (5.40 g, 135.0 mmol) in tetrahydrofuran (60 mL) andwater (30 mL) was heated to reflux overnight. Tetrahydrofuran wasremoved in vacuo, and the residue was neutralized with 5% hydrochloricacid solution to pH 56. The precipitate obtained was collected byfiltration and dried to afford the crude2-amino-4-methylthiazole-5-carboxylic acid (5.20 g, 94%): ¹H NMR (300MHz, DMSO-d₆) δ 7.63 (s, 2H), 2.30 (s, 3H); MS (ES+) m/z 159.1 (M+1).

B. To a suspension of 2-amino-4-methylthiazole-5-carboxylic acid (5.20g, 32.9 mmol) and N,N-diisopropylethylamine (15 mL, 86.7 mmol) inN,N-dimethylformamide (40 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (8.18 g,42.7 mmol). The resulting mixture was stirred for 30 min, then1-hydroxybenzotriazole hydrate (5.78 g, 42.7 mmol) was added, followedby the addition of benzylamine (4.3 mL, 39.3 mmol). The reaction mixturewas stirred at ambient temperature for 2 days, then diluted with ethylacetate, washed with water and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by column chromatography to afford the titlecompound in 60% yield (4.90 g): ¹H NMR (300 MHz, DMSO-d₆) δ 7.36-7.25(m, 5H), 5.79 (br s, 1H), 5.36 (br s, 2H), 4.54 (d, J=5.7 Hz, 2H), 2.47(s, 3H); MS (ES+) m/z 248.4 (M+1).

Preparation 2 Preparation of2-amino-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (4.20 g,26.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added1-hydroxybenzotriazole (9.30 g, 69.0 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (6.60 g, 34.0 mmol),diisopropylethylamine (4.40 g, 34.0 mmol), and(4-fluorophenyl)methanamine (3.97 g, 32.0 mmol). The reaction mixturewas stirred at ambient temperature for 18 hours andN,N-dimethylformamide was removed in vacuo. The residue was dissolved inethyl acetate (400 mL) and washed with saturated aqueous sodiumbicarbonate (2×100 mL) and brine (100 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo to afford the title compound as a yellowish solidin 80% yield (5.60 g): ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.17 (m, 2H), 7.01(t, J=8.3 Hz, 2H), 5.78 (br s, 1H), 5.34 (br s, 2H), 4.50 (d, J=5.6 Hz,2H), 2.47 (s, 3H); MS (ES+) m/z 266.2 (M+1).

Preparation 3 Preparation ofN-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide

To a solution of 4-bromobutyric acid (0.94 g, 5.50 mmol) and4-methylmorpholine (0.70 mL, 6.20 mmol) in tetrahydrofuran (40 mL) wasadded isobutyl chloroformate (0.75 mL, 5.60 mmol) at 0° C. The resultingreaction mixture was stirred at 0° C. for 2 hours and then2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.24 g, 5.00 mmol) wasadded. After 14 hours at ambient temperature, the solvent was removed invacuo, and the residue was dissolved in ethyl acetate (200 mL), washedwith water and brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and the residue was purified by columnchromatography to yield the title compound (1.80 g, 90%): ¹H NMR (300MHz, CDCl₃) δ 7.30-7.23 (m, 5H), 5.99 (s, 1H), 4.57-4.55 (m, 2H),4.34-4.27 (m, 2H), 3.38-3.44 (m, 2H), 2.64-2.18 (m, 5H); MS (ES+) m/z396.3 (M+1) and 398.3 (M+1).

Preparation 4 Preparation of2-(4-bromobutanamido)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

To a solution of 4-bromobutanoic acid (4.40 g, 26.0 mmol) in anhydrousdichloromethane (100 mL) was added two drops of N,N′-dimethylformamide,followed by the addition of oxalyl chloride (4.99 g, 39.0 mmol)dropwise. The reaction was stirred at ambient temperature for 4 hours.The solvent was removed in vacuo to afford 4-bromobutanoyl chloride(4.87 g, 26.0 mmol) as a yellow oil, which was used in the next stepwithout further purification.

To a solution of2-amino-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5.60 g, 22.0mmol) and triethylamine (2.61 g, 26.0 mmol) in anhydrous tetrahydrofuran(250 mL) was added 4-bromobutanoyl chloride (4.99 g, 26.0 mmol) inanhydrous dichloromethane (10 mL) dropwise at 0° C. The reaction mixturewas stirred at ambient temperature for 2 hours, then diluted withdichloromethane (200 mL) and washed with saturated aqueous sodiumbicarbonate solution (2×150 mL), and brine (150 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrate in vacuo to afford the title compound as a yellow oil in 92%yield (8.00 g): ¹H NMR (300 MHz, CDCl₃) δ 8.61 (br s, 1H), 7.32-7.22 (m,2H), 7.05-6.94 (m, 2H), 6.14 (t, J=5.6 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H),3.45 (t, J=6.7 Hz, 2H), 2.65 (t, J=6.7 Hz, 2H), 2.58 (s, 3H), 2.23(quintet, J=6.7 Hz, 2H); MS (ES+) m/z 413.1 (M+1), 415.1 (M+1).

Preparation 5 Preparation of 3-(4-fluorobenzyl)pyrrolidin-2-one

A. To a solution of pyrrolidin-2-one (1.00 g, 12.0 mmol) in anhydroustoluene (20 mL) was added trifluoroacetic anhydride (2.30 mL, 16.0 mmol)dropwise at 0° C. The reaction mixture was stirred at ambienttemperature for 1 hour and concentrated in vacuo. The residue wasevaporated in vacuo with anhydrous toluene (3×20 mL) to afford1-(2,2,2-trifluoroacetyl)pyrrolidin-2-one as a clear oil (2.12 g, 99%):¹H NMR (300 MHz, CDCl₃) δ 3.85 (t, J=7.2 Hz, 2H), 2.61 (t, J=8.1 Hz,2H), 2.22-2.04 (m, 2H).

B. To a suspension of potassium tert-butoxide (2.00 g, 18.0 mmol) inanhydrous tetrahydrofuran (40 mL) was added a mixture of1-(2,2,2-trifluoroacetyl)-pyrrolidin-2-one (2.12 g, 12.0 mmol) and4-fluorobenzaldehyde (1.24 mL, 12.0 mmol) in anhydrous tetrahydrofuran(5 mL) dropwise at 0° C. The reaction mixture was stirred at ambienttemperature for 2 hours, then refluxed for 1 hour and concentrated invacuo. Water (150 mL) was added to the residue. The white solidprecipitated was filtered and re-dissolved in ethyl acetate (50 mL) andthen hydrogenated in the presence of catalytic amount of palladium oncarbon (20% w/w) at ambient temperature and atmospheric pressure for 3hours. The reaction mixture was filtered through a bed of celite. Thefiltrate was concentrated in vacuo and the residue was purified bycolumn chromatography (ethyl acetate) to afford the title compound as awhite solid (0.72 g, 35%): ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.09 (m, 2H),7.00-6.90 (m, 2H), 6.42 (s, 1H), 3.31-3.07 (m, 3H), 2.71-2.54 (m, 2H),2.19-2.03 (m, 1H), 1.89-1.69 (m, 1H); MS (ES+) m/z 194.1 (M+1).

Preparation 6 Preparation of3-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one

Following the procedure as described in Preparation 5, making variationsas required to use 4-(trifluoromethoxy)benzaldehyde in place of4-fluorobenzaldehyde to react with1-(2,2,2-trifluoroacetyl)pyrrolidin-2-one, the title compound wasobtained as a white solid in 53% yield: ¹H NMR (300 MHz, CDCl₃) δ7.24-7.06 (m, 4H), 3.71-3.50 (m, 2H), 3.34-3.02 (m, 3H), 2.19-2.00 (m,1H), 1.83-1.70 (m, 1H); MS (ES+) m/z 260.1 (M+1).

Preparation 7 Preparation of2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide

To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (2.25 g,10.0 mmol) and 4-methylmorpholine (1.25 g, 11.0 mmol) in anhydrousdichloromethane (80 mL) was added isobutylchloroformate (1.33 mL, 10.0mmol) dropwise at 0° C. After stirring at ambient temperature for 2hours, the reaction mixture was cooled to 0° C. andpyridin-3-ylmethanamine (1.23 g, 12.0 mmol) was added dropwise. Thereaction mixture was stirred at ambient temperature for 4 hours, dilutedwith ethyl acetate (100 mL) and washed with saturated aqueous sodiumbicarbonate (50 mL) and brine (50 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and the filtrate was concentrated invacuo. The residue was purified by column chromatography (ethyl acetate)to afford the title compound as a yellow solid (1.78 g, 56%): ¹H NMR(300 MHz, CDCl₃) δ 8.51 (d, J=2.5 Hz, 2H), 7.67 (td, J=7.8, 1.9 Hz, 1H),7.29-7.26 (m, 1H), 6.36 (br s, 1H), 4.56 (d, J=5.9 Hz, 2H), 2.63 (s,3H); MS (ES+) m/z 312.1 (M+1), 314.1 (M+1).

Preparation 8 Preparation ofN-benzyl-2-bromo-4-methylthiazole-5-carboxamide

Following the procedure as described in Preparation 7, making variationsas required to use benzylamine in place of pyridin-3-ylmethanamine toreact with 2-bromo-4-methylthiazole-5-carboxylic acid, the titlecompound was obtained as a yellow solid in 60% yield: ¹H NMR (300 MHz,CDCl₃) δ 7.41-7.26 (m, 5H), 5.99 (br s, 1H), 4.56 (d, J=5.7 Hz, 2H),2.63 (s, 3H); MS (ES+) m/z 311.2 (M+1), 313.2 (M+1).

Preparation 9 Preparation ofN-benzyl-2-(5-bromopentanamido)-4-methylthiazole-5-carboxamide

To a mixture 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.29 g,5.20 mmol) and triethylamine (0.58 g, 5.72 mmol) in anhydrousdichloromethane (25.0 mL) was added dropwise 5-bromopentanoyl chloride(1.141 g, 5.72 mmol) in anhydrous dichloromethane (10 mL) at 0° C. Thereaction mixture was stirred at ambient temperature for 2 hours, thendiluted with dichloromethane (40 mL) and washed with saturated aqueoussodium bicarbonate solution (2×50 mL) and brine (50 mL). The organicphase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrate in vacuo to afford the title compound as ayellow oil (1.91 g, 92%): ¹H NMR (300 MHz, CDCl₃) δ 8.81 (br s, 1H),7.33-7.23 (m, 5H), 5.91 (s, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.51 (t, J=6.7Hz, 2H), 2.46 (s, 3H), 2.35 (t, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.53 (m,2H); MS (ES+) m/z 410.1 (M+1), 412.1 (M+1).

Example 1 Synthesis ofN-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide

To a solution ofN-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide (1.80 g,4.54 mmol) in acetone (50 mL) and water (5 mL) was added potassiumcarbonate (1.50 g, 10.8 mmol) at ambient temperature. The resultingreaction mixture was stirred at ambient temperature for 2 hours. Thesolvent was removed in vacuo, and the residue was washed with water andt-butyl methyl ether to yield the title compound in 78% yield (1.12 g):mp 222-224° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (t, J=6.0 Hz, 1H),7.33-7.16 (m, 5H), 4.35 (d, J=6.0 Hz, 2H), 3.97 (t, J=7.2 Hz, 2H), 2.59(t, J=7.8 Hz, 2H), 2.46 (s, 3H), 2.14-1.94 (m, 2H); MS (ES+) m/z 316.4(M+1).

Example 1.1 Synthesis ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 1, making variations asrequired to use2-(4-bromobutanamido)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamidein replace ofN-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide, the titlecompound was obtained as a white solid in 85% yield: ¹H NMR (300 MHz,CD₃OD) δ 7.39-7.33 (m, 2H), 7.09-7.02 (m, 2H), 4.48 (s, 2H), 4.15-4.09(m, 2H), 2.68 (t, J=8.1 Hz, 2H), 2.55 (s, 3H), 2.25 (m, 2H); MS (ES+)m/z 334.2 (M+1).

Example 1.2 Synthesis ofN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 1, making variations asrequired to useN-benzyl-2-(5-bromopentanamido)-4-methylthiazole-5-carboxamide inreplace ofN-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide, the titlecompound was obtained as a white solid in 35% yield: mp 175-176° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 7.33-7.25 (m, 5H), 5.96 (s, 1H), 4.57 (d, J=5.6Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.64 (s, 3H),2.02-1.87 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 169.8, 162.7, 156.9, 152.0,138.0, 128.8, 127.9, 127.6, 119.4, 48.0, 44.0, 32.7, 22.5, 20.2, 17.4;MS (ES+) m/z 330.6 (M+1).

Example 1.3 Synthesis ofN-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 1, making variations asrequired to use2-(5-bromopentanamido)-N-(3-fluorobenzyl)-4-methylthiazole-5-carboxamidein place ofN-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide, the titlecompound was obtained as a white solid in 85% yield: ¹H NMR (300 MHz,CDCl₃) δ 7.35-7.23 (m, 1H), 7.15-6.91 (m, 3H), 6.08 (t, J=5.6 Hz, 1H),4.55 (d, J=5.6 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.70-2.61 (m, 5H),2.05-1.84 (m, 4H).

Example 2 Synthesis ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide

To a solution ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide(0.13 g, 0.38 mmol) in a mixture of anhydrous tetrahydrofuran and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8/1, v/v) at −78° C.was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL,0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5minutes, followed by the addition of1-(bromomethyl)-4-(trifluoromethyl)benzene (0.058 mL, 0.38 mmol)dropwise. The reaction mixture was warmed to −30° C. in 30 minutes.Aqueous saturated ammonium chloride solution (10 mL) was added, followedby extraction with dichloromethane (3×10 mL). The combined organicsolutions were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(ethyl acetate/hexanes (1/1)) to afford the title compound as a whitesolid (0.075 g, 41%): mp 175-176° C. (hexanes/ethyl acetate); ¹H NMR(300 MHz, CDCl₃) δ 7.53 (d, J=7.9 Hz, 2H), 7.32-7.24 (m, 4H), 7.01 (t,J=8.9 Hz, 2H), 6.03 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.17-4.04(m, 1H), 3.91-3.81 (m, 1H), 3.30 (dd, J=13.8, 4.3 Hz, 1H), 3.06-2.99 (m,1H), 2.85 (dd, J=13.8, 8.9 Hz, 1H), 2.61 (s, 3H), 2.32-2.21 (m, 1H),1.93-1.83 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 174.4, 162.3, 155.3, 152.8,142.4, 133.8, 129.9, 129.6, 129.3, 125.6, 118.6, 115.7, 115.6, 45.9,44.2, 43.4, 36.2, 24.4, 17.3; MS (ES+) m/z 492.3 (M+1).

Example 2.1 Synthesis ofN-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to use 1-(bromomethyl)-4-fluorobenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene to react withN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide,the title compound was obtained as a white solid in 36% yield: mp196-197° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.26(m, 2H), 7.13 (dd, J=8.6, 5.6 Hz, 2H), 7.06-6.90 (m, 4H), 6.03 (t, J=5.6Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.06-3.95 (m, 1H), 3.95-3.70 (m, 1H),3.29-3.10 (m, 1H), 3.05-2.92 (m, 1H), 2.88-2.70 (m, 1H), 2.60 (s, 3H),2.32-2.17 (m, 1H), 2.00-1.80 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 174.8,176.3, 162.3, 161.8, 155.4, 152.9, 133.8, 133.7, 130.4, 129.6, 118.5,115.7, 115.5, 45.9, 44.4, 43.4, 35.6, 24.2, 17.3; MS (ES+) m/z 442.2(M+1).

Example 2.2 Synthesis of2-(3-(4-(difluoromethoxy)benzyl)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to use 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene to react withN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide,the title compound was obtained as a white solid in 31% yield: mp143-145° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.22(m, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.06-6.93 (m, 4H), 6.45 (t, J=73.9 Hz,1H), 6.08 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.09-3.99 (m, 1H),3.91-3.78 (m, 1H), 3.25-3.12 (m, 1H), 3.05-2.94 (m, 1H), 2.83-2.73 (m,1H), 2.59 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.81 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 174.7, 162.3, 162.2, 160.6, 155.4, 152.7, 149.9, 135.4,133.8, 130.3, 129.6, 119.8, 115.6, 112.4, 45.9, 44.3, 43.3, 35.6, 24.2,17.2; MS (ES+) m/z 490.3 (M+1).

Example 2.3 Synthesis ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to use 1-(bromomethyl)-4-(trifluoromethoxy)benzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene to react withN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide,the title compound was obtained as a white solid in 26% yield: mp165-166° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.16(m, 4H), 7.12 (d, J=8.6 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.02 (t, J=5.6Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.09-4.02 (m, 1H), 3.93-3.79 (m, 1H),3.29-3.20 (m, 1H), 3.05-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.60 (s, 3H),2.35-2.19 (m, 1H), 1.99-1.81 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 174.6,162.3, 155.4, 152.8, 148.1, 136.9, 133.7, 131.6, 130.3, 129.6, 121.2,118.6, 115.7, 45.9, 44.3, 43.4, 35.7, 24.3, 17.2; MS (ES+) m/z 508.3(M+1).

Example 2.4 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide inplace ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the titlecompound was obtained as a white solid in 27% yield: mp 174-175° C.(hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.0 Hz,2H), 7.39-7.20 (m, 7H), 6.01 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H),4.14-4.02 (m, 1H), 3.93-3.79 (m, 1H), 3.35-3.24 (m, 1H), 3.09-2.96 (m1H), 2.90-2.80 (m, 1H), 2.61 (s, 3H), 2.34-2.19 (m, 1H), 1.95-1.81 (m,1H); ¹³C NMR (75 MHz, CDCl₃) δ 174.4, 162.3, 155.3, 152.6, 142.4, 137.8,129.3, 128.8, 127.9, 127.7, 125.7, 125.6, 125.5, 118.8, 45.9, 44.2,44.1, 36.2, 24.4, 17.2; MS (ES+) m/z 474.1 (M+1).

Example 2.5 Synthesis ofN-benzyl-2-(3-(4-(difluoromethoxy)benzyl)-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide inplace ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 27% yield: mp 132-133° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.24 (m, 5H), 7.18 (d, J=8.2Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 6.46 (dt, J=73.9, 1.0 Hz, 1H), 5.94 (t,J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.11-3.98 (m, 1H), 3.93-3.81 (m,1H), 3.28-3.16 (m, 1H), 3.08-2.93 (m, 1H), 2.80 (dd, J=13.7, 8.8 Hz,1H), 2.62 (s, 3H), 2.33-2.19 (m, 1H), 1.99-1.84 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 174.6, 162.3, 155.3, 152.7, 137.8, 135.4, 130.3, 128.8,127.9, 127.7, 119.9, 119.5, 118.7, 115.9, 45.9, 44.4, 44.1, 35.6, 24.2,17.3; MS (ES+) m/z 472.3 (M+1).

Example 2.6 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)piperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the titlecompound was obtained as a white solid in 47% yield: mp 217-218° C.(hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.1 Hz,2H), 7.38-7.21 (m, 7H), 6.02 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H),4.35-4.24 (m, 1H), 3.98-3.89 (m, 1H), 3.49-3.41 (m, 1H), 2.93-2.74 (m,2H), 2.63 (s, 3H), 2.12-1.68 (m, 3H), 1.62-1.42 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 171.6, 162.6, 156.9, 152.1, 143.2, 137.9, 129.6, 128.8,127.9, 127.7, 125.9, 125.5, 125.4, 119.9, 47.9, 44.1, 43.9, 37.3, 24.9,21.3, 17.4; MS (ES+) m/z 488.1 (M+1).

Example 2.7 Synthesis ofN-benzyl-4-methyl-2-(3-(4-methylbenzyl)-2-oxopiperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-methylbenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 53% yield: mp 110-113° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.22 (m, 5H), 7.12-6.99 (m,4H), 6.09 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.28-4.19 (m, 1H),3.99-3.86 (m, 1H), 3.43-3.29 (m, 1H), 2.82-2.66 (m, 2H), 2.63 (s, 3H),2.29 (s, 3H), 2.06-1.69 (m, 3H), 1.61-1.43 (m, 1H); ¹³C NMR (75 MHz,CDCl₃) δ 172.2, 162.7, 157.0, 152.1, 138.0, 136.1, 135.8, 129.2, 129.1,128.8, 127.9, 127.6, 119.4, 48.1, 44.2, 44.0, 37.1, 24.8, 21.2, 21.1,17.4; MS (ES+) m/z 434.3 (M+1).

Example 2.8 Synthesis ofN-benzyl-2-(3-(3-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-3-fluorobenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 89% yield: mp 170-171° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.17 (m, 6H), 6.99-6.89 (m,3H), 6.01 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.33-4.21 (m, 1H),3.99-3.89 (m, 1H), 3.45-3.36 (m, 1H), 3.86-3.27 (m, 2H), 2.63 (s, 3H),2.10-1.96 (m, 1H), 1.94-1.73 (m, 2H), 1.61-1.43 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 171.8, 162.9, 162.6, 156.9, 152.1, 141.6, 137.9, 130.1,128.8, 127.9, 127.7, 124.9, 119.5, 114.9, 114.6, 113.6, 48.0, 44.0,37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 438.2 (M+1).

Example 2.9 Synthesis ofN-benzyl-2-(3-(4-methoxybenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-methoxybenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 28% yield: mp 116-118° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.23 (m, 5H), 7.08 (d, J=8.5Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.00 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6Hz, 2H), 4.29-4.20 (m, 1H), 3.97-3.88 (m, 1H), 3.76 (s, 3H), 3.37-3.27(m, 1H), 2.82-2.67 (m, 2H), 2.63 (s, 3H), 2.08-1.93 (m, 1H), 1.92-1.71(m, 2H), 1.62-1.44 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 166.3, 156.7,152.3, 151.1, 146.2, 131.9, 124.9, 124.2, 122.9, 121.9, 121.7, 113.4,107.9, 49.3, 42.2, 38.3, 38.1, 30.7, 18.8, 15.3, 11.4; MS (ES+) m/z450.2 (M+1).

Example 2.10 Synthesis ofN-benzyl-2-(3-(2,5-difluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 2-(bromomethyl)-1,4-difluorobenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 32% yield: mp 144-145° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.22 (m, 5H), 7.02-6.81 (m,3H), 6.01 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.32-4.20 (m, 1H),4.03-3.94 (m, 1H), 3.47-3.37 (m, 1H), 2.90-2.73 (m, 2H), 2.63 (s, 3H),2.12-1.98 (m, 1H), 1.96-1.75 (m, 2H), 1.64-1.45 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 171.5, 162.6, 160.2, 158.6, 157.3, 156.9, 152.2, 137.9,128.8, 127.9, 127.5, 119.6, 117.7, 116.3, 114.7, 47.9, 44.1, 43.0, 30.6,24.9, 21.3, 17.3; MS (ES+) m/z 456.2 (M+1).

Example 2.11 Synthesis ofN-benzyl-2-(3-benzyl-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with (bromomethyl)benzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 26% yield: mp 162-164° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.32 (m, 10H), 6.01 (br s, 1H),4.57 (d, J=5.3 Hz, 2H), 4.32-4.18 (m, 1H), 4.02-3.88 (m, 1H), 3.47-3.38(m, 1H), 2.87-2.69 (m, 2H), 2.64 (s, 3H), 2.07-1.45 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 172.2, 162.7, 157.0, 152.2, 138.9, 137.9, 129.2, 128.8,128.6, 127.9, 127.7, 126.5, 119.4, 48.1, 44.1, 44.0, 37.6, 24.8, 21.2,17.4; MS (ES+) m/z 420.5 (M+1).

Example 2.12 Synthesis ofN-benzyl-2-(3-(4-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-fluorobenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 61% yield: mp 154-155° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.21 (m, 5H), 7.12-7.07 (m,2H), 6.99-6.88 (m, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H),4.29-4.16 (m, 1H), 3.97-3.82 (m, 1H), 3.39-3.25 (m, 1H), 2.82-2.66 (m,2H), 2.61 (s, 3H), 2.06-1.91 (m, 1H), 1.89-1.69 (m, 2H), 1.57-1.41 (m,1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.9, 162.7, 161.6, 156.9, 151.9, 138.0,134.6, 130.6, 128.8, 127.9, 127.6, 119.6, 115.3, 48.0, 44.1, 44.0, 36.7,24.8, 21.2, 17.4; MS (ES+) m/z 438.2 (M+1).

Example 2.13 Synthesis ofN-(3-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamidein place ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-fluorobenzene in place of1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound wasobtained as a white solid in 46% yield: mp 173-175° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.24 (m, 1H), 7.15-6.88 (m,7H), 6.12 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.29-4.21 (m, 1H),3.98-3.86 (m, 1H), 3.40-3.27 (m, 1H), 2.86-2.69 (m, 2H), 2.62 (s, 3H),2.08-1.95 (m, 1H), 1.93-1.73 (m, 2H), 1.61-1.44 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 171.9, 162.9, 162.6, 161.6, 156.9, 152.4, 140.6, 134.5,130.5, 130.2, 123.2, 119.1, 115.3, 114.6, 114.4, 47.9, 44.1, 43.4, 36.6,24.8, 21.2, 17.3; MS (ES+) m/z 456.3 (M+1).

Example 2.14 Synthesis ofN-(3-fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)piperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 2, making variation asrequired to useN-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamidein place ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the titlecompound was obtained as a white solid in 41% yield: mp 177-178° C.(hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.1 Hz,2H), 7.30-7.27 (m, 3H), 7.10-6.92 (m, 3H), 6.11 (t, J=5.6 Hz, 1H), 4.56(d, J=5.6 Hz, 2H), 4.33-4.21 (m, 1H), 4.00-3.88 (m, 1H), 3.53-3.56 (m,1H), 2.94-2.73 (m, 2H), 2.62 (s, 3H), 2.11-1.95 (m, 1H), 1.94-1.75 (m,2H), 1.62-1.43 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.7, 162.9, 162.7,156.9, 152.4, 143.2, 140.6, 130.3, 129.6, 128.9, 125.9, 125.5, 125.4,123.3, 122.4, 119.3, 114.7, 114.5, 48.0, 43.9, 43.3, 37.3, 24.9, 21.3,17.4; MS (ES+) m/z 506.3 (M+1).

Example 3 Synthesis of2-(3-(cyclopropylmethyl)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

To a solution ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide(0.13 g, 0.38 mmol) in a mixture of anhydrous tetrahydrofuran and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8/1, v/v) at −78° C.was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL,0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5minutes, followed by the addition of cyclopropanecarbaldehyde (0.028 mL,0.38 mmol) dropwise. The reaction mixture was warmed to ambienttemperature after 3 hours followed by the addition of aqueous saturatedammonium chloride (10 mL) solution. The mixture was extracted withdichloromethane (3×10 mL). The combined organic solutions were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and hydrogenated in the presenceof catalytic amount of Pd/C (20% w/w) at ambient temperature andatmospheric pressure for 1 hour. The reaction mixture was filteredthrough a bed of celite and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography (ethyl acetate/hexanes(1/1)) to afford the title compound as a white solid (0.025 g, 17%): mp153-155° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.23(m, 2H), 7.01 (t, J=8.6 Hz, 2H), 5.95 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6Hz, 2H), 4.23-4.14 (m, 1H), 3.99-3.90 (m, 1H), 2.87-2.78 (m, 1H), 2.62(s, 3H), 2.53-2.42 (m, 1H), 2.08-1.94 (m, 1H), 1.79-1.69 (m, 1H),1.52-1.42 (m, 1H), 0.84-0.69 (m, 1H), 0.53-0.39 (m, 2H), 0.16-0.03 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 175.9, 162.4, 162.3, 155.5, 152.9, 133.7,129.6, 118.2, 115.7, 46.2, 43.3, 35.5, 24.9, 17.3, 8.6, 4.8, 4.3; MS(ES+) m/z 388.2 (M+1).

Example 3.1 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-phenethylpiperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 3, making variations asrequired to use 2-phenylacetaldehyde in place ofcyclopropanecarbaldehyde to react withN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide,the title compound was obtained as a white solid in 24% yield: mp124-126° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.09(m, 10H), 5.98 (t, J=5.4 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.29-4.20 (m,1H), 4.07-4.04 (m, 1H), 2.83-2.66 (m, 2H), 2.64 (s, 3H), 2.61-2.48 (m,1H), 2.41-2.26 (m, 1H), 2.17-2.01 (m, 2H), 1.96-1.76 (m, 2H), 1.74-1.58(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 162.7, 156.9, 152.2, 141.3,137.9, 128.8, 128.5, 128.4, 127.9, 127.6, 126.1, 119.1, 47.9, 44.1,41.4, 33.3, 33.0, 25.7, 21.3, 17.4; MS (ES+) m/z 434.1 (M+1).

Example 3.2 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(3-phenylpropyl)piperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 3, making variations asrequired to use 3-phenylpropanal in place of cyclopropanecarbaldehyde toreact withN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide,the title compound was obtained as a white solid in 10% yield: mp140-141° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.10(m, 10H), 5.98 (t, J=4.7 Hz, 1H), 4.55 (d, J=5.3 Hz, 2H), 4.31-4.19 (m,1H), 4.04-3.91 (m, 1H), 2.69-2.47 (m, 6H), 2.11-1.78 (m, 4H), 1.76-1.53(m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 162.7, 157.0, 152.2, 142.0,137.9, 128.8, 128.4, 128.3, 127.9, 127.6, 125.9, 119.2, 47.9, 44.1,42.2, 35.9, 31.4, 28.9, 25.5, 21.3, 17.4; MS (ES+) m/z 448.21 (M+1).

Example 4 Synthesis of2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

To a solution ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide(0.35 g, 1.05 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. wasadded lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.31 mL, 2.31mmol) dropwise. The reaction mixture was stirred at −78° C. for 5minutes, followed by the addition of N-bromosuccinimide (0.19 g, 1.05mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 min,quenched with aqueous saturated ammonium chloride solution (10 mL) andextracted with dichloromethane (3×10 mL). The combined organic solutionswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography eluting withethyl acetate/hexanes (1/1) to afford the title compound as a whitesolid (0.22 g, 51%): ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.24 (m, 2H),7.07-6.97 (m, 2H), 5.98 (b s, 1H), 4.66-4.59 (m, 1H), 4.58 (d, J=5.8 Hz,2H), 4.30-4.14 (m, 2H), 2.86-2.69 (m, 1H), 2.64 (s, 3H), 2.56-2.45 (m,1H); MS (ES+) m/z 412 (M+1), 414 (M+1).

Example 4.1 Synthesis ofN-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 4, making variations asrequired to useN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in placeofN-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamideto react with N-bromosuccinimide, the title compound was obtained as ayellow oil in 56% yield: MS (ES+) m/z 408.2 (M+1), 410.2 (M+1).

Example 5 Synthesis of2-(3-(2-cyclopropylethylamino)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide

To a solution of2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide(0.050 g, 0.12 mmol) in a mixture of tetrahydrofuran and water (1/0.1,v/v) was added potassium carbonate (0.034 g, 0.24 mmol) and2-cyclopropylethanamine (0.012 g, 0.15 mmol). The reaction mixture wasstirred at ambient temperature for 17 hours and concentrated in vacuo.The residue was purified by column chromatography (ethyl acetate/hexanes(3/1)) to afford the title compound as a white solid (0.030g, 60%): mp151-152° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.22(m, 2H), 7.05-6.96 (m, 2H), 6.01 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz,2H), 4.27-4.17 (m, 1H), 3.93-3.81 (m, 1H), 3.76-3.66 (m, 1H), 2.88-2.67(m, 2H), 2.61 (s, 3H), 2.58-2.44 (m, 1H), 2.10-1.91 (m, 1H), 1.52-1.29(m, 2H), 0.75-0.59 (m, 1H), 0.49-0.37 (m, 2H), 0.08-0.01 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 173.6, 162.3, 162.2, 155.2, 152.9, 133.7, 129.6,118.6, 115.6, 59.5, 47.9, 44.9, 43.4, 35.0, 26.9, 17.3, 8.8, 4.4, 4.2;MS (ES+) m/z 417.3 (M+1).

Example 5.1 Synthesis ofN-(4-fluorobenzyl)-2-(3-(4-fluorobenzylamino)-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 5, making variation asrequired to use (4-fluorophenyl)methanamine in place of2-cyclopropylethanamine to react with2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide,the title compound was obtained as a white solid in 85% yield: mp123-124° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.21(m, 4H), 7.06-6.92 (m, 4H), 6.07 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.6 Hz,2H), 4.20 (t, J=5.6 Hz, 1H), 3.97-3.76 (m, 3H), 3.68 (t, J=8.6 Hz, 1H),2.60 (s, 3H), 2.53-2.37 (m, 1H), 2.11-1.89 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 173.6, 162.3, 162.2, 162.1, 155.2, 152.8, 135.0, 133.7, 129.8,129.6, 118.8, 115.6, 115.4, 58.5, 51.0, 44.8, 43.3, 27.1, 17.3; MS (ES+)m/z 457.3 (M+1).

Example 5.2 Synthesis ofN-(4-fluorobenzyl)-4-methyl-2-(2-oxo-3-(3,3,3-trifluoropropylamino)pyrrolidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 5, making variation asrequired to use 3,3,3-trifluoropropan-1-amine in place of2-cyclopropylethanamine to react with2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide,the title compound was obtained as a white solid in 19% yield: mp142-143° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 7.35 (m,2H), 7.07-6.93 (m, 2H), 6.00 (br s, 1H), 4.51 (d, J=5.4 Hz, 2H),4.29-4.16 (m, 1H), 3.65-3.81 (m, 1H), 3.76-3.64 (m, 1H), 3.15-3.02 (m,1H), 2.98-2.85 (m, 1H), 2.61 (s, 3H), 2.60-2.48 (m, 1H), 2.43-2.22 (m,2H), 2.08-1.89 (m, 1H), 1.79 (br s, 1H); MS (ES+) m/z 445.3 (M+1).

Example 5.3 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzylamino)piperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 5, making variation asrequired to use (4-(trifluoromethyl)phenyl)methanamine in place of2-cyclopropylethanamine to react withN-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamidein place of2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide,the title compound was obtained as a white solid in 20% yield: mp 39-40°C. (diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.1 Hz, 2H),7.45 (d, J=8.1 Hz, 2H), 7.39-7.21 (m, 5H), 6.03 (t, J=5.6 Hz, 1H), 4.55(d, J=5.6 Hz, 2H), 4.32-4.21 (m, 1H), 4.06-3.96 (m, 1H), 3.93 (s, 2H),3.50-3.39 (m, 1H), 2.62 (s, 3H), 2.30-2.05 (m, 2H), 1.99-1.83 (m, 2H),1.81-1.66 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 162.5, 156.6, 152.0,143.8, 137.9, 129.4, 128.8, 128.3, 127.9, 127.7, 125.5, 125.4, 119.7,57.9, 50.9, 47.5, 44.1, 26.5, 20.4, 17.4; MS (ES+) m/z 503.3 (M+1).

Example 5.4 Synthesis ofN-benzyl-2-(3-(cyclopropylmethylamino)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 5, making variation asrequired to use cyclopropylmethanamine in place of2-cyclopropylethanamine to react withN-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamidein place of2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide,the title compound was obtained as a white solid in 69% yield: mp125-126° C. (diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.29 (m,5H), 5.95 (t, J=5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 4.37-4.26 (m, 1H),4.04-3.91 (m, 1H), 3.54-3.45 (m, 1H), 2.63 (s, 3H), 2.59-2.44 (m, 2H),2.31-1.82 (m, 4H), 1.81-1.68 (m, 1H), 1.01-0.89 (m, 1H), 0.57-0.41 (m,2H), 0.23-0.08 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 162.5, 156.7,152.2, 137.9, 128.8, 127.9, 127.7, 119.6, 58.5, 52.5, 47.6, 44.1, 26.4,20.5, 17.4, 11.2, 3.6, 3.3; MS (ES+) m/z 399.3 (M+1).

Example 6 Synthesis ofN-benzyl-2-(4-benzyl-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

A mixture of 4-benzylpyrrolidin-2-one (0.068 g, 0.39 mmol),N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.10 g, 0.32 mmol),cesium carbonate (0.16 g, 0.48 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.006 g, 0.060 mmol) andxantphos (0.008 g, 0.013 mmol) in anhydrous toluene (3 mL) was subjectedto microwave irradiation at 120° C. for 15 min. The reaction mixture wasconcentrated in vacuo and the residue was purified by columnchromatography (ethyl acetate/hexanes (1/1)) to afford the titlecompound as a white solid (0.017 g, 13%): mp 143-144° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.11 (m, 10H), 5.91 (br s, 1H),4.56 (d, J=5.5 Hz, 2H), 4.25-4.13 (m, 1H), 3.85-3.72 (m, 1H), 2.95-2.68(m, 4H), 2.61 (s, 3H), 2.52-2.39 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ173.0, 162.3, 155.3, 152.6, 138.2, 137.9, 128.8, 128.7, 127.9, 127.6,126.8, 118.6, 52.6, 44.0, 40.1, 37.7, 33.4, 17.2; MS (ES+) m/z 406.3(M+1).

Example 7 Synthesis of(S)—N-benzyl-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

A. To a solution of (S)-4-hydroxypyrrolidin-2-one (1.00 g, 9.89 mmol) inanhydrous dichloromethane (40 mL) was added 3,4-dihydro-2H-pyrane (1.35mL, 14.84 mmol) and pyridiniump-toluenesulfonate (0.25 g, 0.99 mmol).The reaction mixture was stirred at ambient temperature for 18 hours,diluted with diethyl ether (100 mL) and washed with brine (25 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to afford(4S)-4-(2-oxotetrahydro-2H-pyran-4-yloxy)pyrrolidin-2-one as a clear oil(1.20 g, 61%): ¹H NMR (300 MHz, CDCl₃) δ 6.60 (br s, 1H), 4.98-4.57 (m,1H), 4.57-4.46 (m, 1H), 3.89-3.70 (m, 1H), 3.68-3.22 (m, 3H), 2.69-2.22(m, 2H), 1.89-1.50 (m, 6H).

B. A mixture of(4S)-4-(2-oxotetrahydro-2H-pyran-4-yloxy)pyrrolidin-2-one (0.036 g, 0.19mmol), N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.050 g, 0.16mmol), cesium carbonate (0.079 g, 0.24 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (0.003 g, 0.003 mmol) and xantphos (0.004 g,0.006 mmol) in anhydrous toluene (3 mL) was subjected to microwaveirradiation at 80° C. for 20 min. The reaction mixture was diluted withethyl acetate (10 mL) and washed with water (4 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was dissolved in ethanol and a catalytic amount ofpyridinium p-toluenesulfonate was added to the solution. The reactionmixture was heated at 50° C. for 6 hours and concentrated in vacuo. Theresidue was dissolved in dichloromethane (15 mL) and washed with water(5 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The obtained white solid was washedwith diethyl ether (25 mL) and dried in air to afford the title compound(0.028 g, 53%): mp 203-204° C. (diethyl ether); ¹H NMR (300 MHz,DMSO-d₆) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.17 (m, 5H), 5.46 (d, J=3.8 Hz,1H), 4.47-4.41 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.12-4.04 (m, 1H),3.93-3.85 (m, 1H), 3.00-2.90 (m, 1H), 2.48 (s, 3H), 2.42-2.33 (m, 1H);¹³C NMR (75 MHz, DMSO-d₆) δ 173.3, 162.1, 155.9, 140.0, 128.7, 127.7,127.2, 119.4, 63.6, 57.0, 43.1, 41.7, 17.5; MS (ES+) m/z 332.2 (M+1).

Example 7.1 Synthesis of(R)—N-benzyl-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 7, making variations asrequired to use (R)-4-hydroxypyrrolidin-2-one in place of(S)-4-hydroxypyrrolidin-2-one, the title compound was obtained as awhite solid in 53% yield: mp 203-204° C. (diethyl ether); ¹H NMR (300MHz, DMSO-d₆) δ 8.60 (t, J=6.0 Hz, 1H), 7.33-7.17 (m, 5H), 5.46 (d,J=6.0 Hz, 1H), 4.48-4.40 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.12-4.04 (m,1H), 3.93-3.85 (m, 1H), 3.00-2.90 (m, 1H), 2.48 (s, 3H), 2.42-2.33 (m,1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 173.3, 162.1, 155.9, 140.0, 128.7,127.7, 127.2, 119.4, 63.6, 57.0, 43.1, 41.7, 17.5 MS (ES+) m/z 332.2(M+1).

Example 8 Synthesis of2-(3-(4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide

A mixture of 3-(4-fluorobenzyl)pyrrolidin-2-one (0.074 g, 0.39 mmol),2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.10 g,0.32 mmol), cesium carbonate (0.16 g, 0.48 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (0.005 g, 0.006 mmol) and xantphos (0.007 g,0.013 mmol) in anhydrous toluene (2 mL) was subjected to microwaveirradiation at 80° C. for 35 min. The reaction mixture was concentratedin vacuo and the residue was purified by column chromatography (ethylacetate/hexanes (3/1)) to afford the title compound as a white solid(0.045 g, 33%): mp 169-170° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz,CDCl₃) δ 8.59 (s, 1H), 8.52 (d, J=4.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),7.30-7.23 (m, 1H), 7.14 (dd, J=8.0, 5.5 Hz, 2H), 6.95 (t, J=8.8 Hz, 2H),6.16 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.07-3.95 (m, 1H),3.92-3.79 (m, 1H), 3.20 (dd, J=13.9, 4.5 Hz, 1H), 3.07-2.93 (m, 1H),2.83-2.74 (m, 1H), 2.61 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.82 (m, 1H);¹³C NMR (75 MHz, CDCl₃) δ 174.8, 163.4, 162.5, 155.5, 153.2, 149.3,149.1, 135.7, 133.8, 133.7, 130.4, 123.7, 118.2, 115.6, 45.9, 44.4,41.5, 35.6, 24.2, 17.3; MS (ES+) m/z 425.3 (M+1).

Example 8.1 Synthesis of4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)pyrrolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide

Following the procedure as described in Example 8, making variations asrequired to use 3-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one in placeof 3-(4-fluorobenzyl)pyrrolidin-2-one to react with2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the titlecompound was obtained as a white solid in 34% yield: mp 158-160° C.(hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.49(d, J=4.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.43 (t,J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.06 (ddd, J=11.5, 8.0, 3.1 Hz,1H), 3.86 (td, J=11.5, 8.0 Hz, 1H), 3.23 (dd, J=13.9, 4.4 Hz, 1H),3.08-2.94 (m, 1H), 2.83-2.74 (m, 1H), 2.60 (s, 3H), 2.34-2.19 (m, 1H),1.94-1.87 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 174.6, 162.5, 155.4, 153.2,149.3, 148.9, 148.0, 138.1, 136.9, 135.7, 133.9, 130.3, 123.7, 121.2,118.3, 45.9, 44.3, 41.5, 35.7, 24.3, 17.3; MS (ES+) m/z 491.3 (M+1).

Example 9 Synthesis ofN-benzyl-2-(2,6-dioxo-4-phenylpiperidin-1-yl)-4-methylthiazole-5-carboxamide

To a stirred solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide(0.50 g, 2.0 mmol) in chloroform (15 mL) with triethylamine (1.8 mL,10.0 mmol) was added 3-phenylpentanedioyl dichloride (0.45 g, 1.84mmol). The mixture was stirred at ambient temperature for 2 h, washedwith 20% hydrochloric acid solution (20 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was crystallized from ethyl acetate/hexane to afford a solid,which was washed with cold methanol and dried in air to afford the titlecompound (0.46 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.20 (m, 10H),6.07 (br s, 1H), 4.60 (d, J=5.6 Hz, 2H), 3.60-3.50 (m, 1H), 3.13 (dd,J=17.1, 4.2 Hz, 2H), 2.95 (dd, J=17.1, 12.0 Hz, 2H), 2.68 (s, 3H); MS(ES+) m/z 420.1 (M+1).

Example 10 Synthesis ofN-benzyl-2-(3-(hydroxy(phenyl)methyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

To a solution ofN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide (0.25 g,0.76 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. was addedlithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol)dropwise. The reaction mixture was stirred at −78° C. for 5 minutes,followed by the dropwise addition of benzaldehyde (0.077 mL, 0.76 mmol).The resulting mixture was slowly warmed to −30° C. over 30 minutes,followed by the addition of water (5 mL) and extraction withdichloromethane (3×10 mL). The combined organic solution was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by column chromatography (ethylacetate/hexanes (1/1)) to afford the title compound as a white solid(0.010g, 3%): mp 74-75° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz,CDCl₃) δ 7.42-7.22 (m, 10H), 6.01 (t, J=5.5 Hz, 1H), 5.63 (d, J=2.5 Hz,1H), 4.57 (d, J=5.5 Hz, 2H), 4.38-4.30 (m, 1H), 3.91-3.81 (m, 1H),2.88-2.82 (m, 1H), 2.63 (s, 3H), 2.09-1.51 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 171.7, 162.6, 152.0, 141.4, 137.9, 128.8, 128.6, 128.4, 127.9,127.7, 127.5, 125.8, 119.7, 72.7, 49.8, 48.0, 44.1, 21.6, 19.4, 17.3; MS(ES+) m/z 436.2 (M+1).

Example 10.1 Synthesis ofN-benzyl-2-(3-((5-ethylthiophen-2-yl)methylene)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide

Following the procedure as described in Example 10, making variations asrequired to use 5-ethylthiophene-2-carbaldehyde in place of benzaldehydeto react withN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, thetitle compound was obtained as a white solid in 14% yield: mp 171-172°C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 8.05 (s, 1H),7.42-7.22 (m, 5H), 7.16 (d, J=3.7 Hz, 1H), 6.83 (dd, J=0.7, 3.7 Hz, 1H),5.98 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.25 (m, 2H),2.93-2.81 (m, 4H), 2.65 (s, 3H), 2.15-2.02 (m, 2H), 1.32 (t, J=7.5 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.8, 162.7, 157.5, 153.7, 152.4, 137.9,136.4, 133.6, 132.9, 128.8, 127.9, 127.6, 124.5, 122.7, 119.5, 46.9,44.1, 25.9, 23.8, 21.9, 17.4, 15.7; MS (ES+) m/z 452.1 (M+1).

Example 10.2 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethylene)piperidin-1-yl)thiazole-5-carboxamide

Following the procedure as described in Example 10, making variations asrequired to use nicotinaldehyde in place of benzaldehyde to react withN-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, thetitle compound was obtained as a white solid in 17% yield: mp 206-208°C. (ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 8.69 (br s, 1H), 8.54 (brs, 1H), 7.91 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.39-7.21 (m, 6H), 6.26(t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.22 (m, 2H), 2.93-2.82(m, 2H), 2.64 (s, 3H), 2.09-1.96 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ163.8, 162.6, 157.3, 152.3, 150.7, 149.4, 138.0, 136.8, 135.5, 130.5,128.8, 127.9, 127.6, 123.5, 120.1, 47.4, 44.0, 25.9, 22.2, 17.4; MS(ES+) m/z 419.2 (M+1).

Example 11 Synthesis ofN-benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethyl)piperidin-1-yl)thiazole-5-carboxamide

A solution ofN-benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethylene)piperidin-1-yl)thiazole-5-carboxamide(0.024 g, 0.053 mmol) in ethyl acetate (10 mL) was hydrogenated in thepresence of catalytic amount of palladium on carbon (20% w/w) at ambienttemperature and under atmospheric pressure for 3 hours. The reactionmixture was filtered through a bed of celite and the filtrate wasconcentrated in vacuo. The residue was recrystallized from hexanes/ethylacetate to afford the title compound as a yellow solid (0.022 g, 92%):mp 140-141° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz, CDCl₃) δ 8.44(br s, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.42-7.16 (m, 6H), 6.07 (br s, 1H),4.57 (d, J=5.6 Hz, 2H), 4.33-4.21 (m, 1H), 3.98-3.86 (m, 1H), 3.43-3.29(m, 1H), 3.91-3.73 (m, 2H), 2.62 (s, 3H), 2.11-2.98 (m, 1H), 1.96-1.74(m, 2H), 1.62-1.45 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 162.6,156.8, 152.1, 150.4, 147.9, 137.9, 136.9, 128.8, 128.7, 127.9, 127.6,123.6, 119.6, 47.9, 44.1, 43.8, 34.6, 24.9, 21.3, 17.4; MS (ES+) m/z421.1 (M+1).

Example 12 Measuring Stearoyl-CoA Desaturase Inhibition Activity of aTest Compound Using Mouse Liver Microsomes

The identification of compounds of the invention as SCD inhibitors wasreadily accomplished using the SCD microsomal assay procedure describedin Shanklin J. and Summerville C., Proc. Natl. Acad. Sci. USA (1991),Vol. 88, pp. 2510-2514.

Preparation of Mouse Liver Microsomes:

Male ICR outbread mice, on a high-carbohydrate, low fat diet, underlight halothane (15% in mineral oil) anesthesia are sacrificed byexsanguination during periods of high enzyme activity. Livers areimmediately rinsed with cold 0.9% NaCl solution, weighed and minced withscissors. All procedures are performed at 4° C. unless specifiedotherwise. Livers are homogenized in a solution (1/3 w/v) containing0.25 M sucrose, 62 mM potassium phosphate buffer (pH 7.0), 0.15 M KCl,15 mM N-acetyleysteine, 5 mM MgCl₂, and 0.1 mM EDTA using 4 strokes of aPotter-Elvehjem tissue homogenizer. The homogenate is centrifuged at10,400×g for 20 min to eliminate mitochondria and cellular debris. Thesupernatant is filtered through a 3-layer cheesecloth and centrifuged at105,000×g for 60 min. The microsomal pellet is gently resuspended in thesame homogenization solution with a small glass/teflon homogenizer andstored at −70° C. The absence of mitochondrial contamination isenzymatically assessed. The protein concentration is measured usingbovine serum albumin as the standard.

Incubation of Mouse Liver Microsomes with Test Compounds:

Desaturase activity is measured as the release of ³H₂O from[9,10-³H]stearoyl-CoA. Reactions per assay point conditions are asfollows: 2 μL 1.5 mM stearoyl-CoA, 0.25 μL 1 mCi/mL ³H stearoyl CoA, 10μL 20 mM NADH, 36.75 μL 0.1 M PK buffer (K₂HPO₄/NaH₂PO₄, pH 7.2). Thetest compound or control solution is added in a 1 μL volume. Reactionsare started by adding 50 μL of microsomes (1.25 mg/mL). The plates aremixed and after 15 min incubation on a heating block (25° C.), thereactions are stopped by the addition of 10 μL 60% PCA. An aliquot of100 μL is then transferred to a filter plate pretreated with charcoaland the plate centrifuged at 4000 rpm for 1 min. The flow throughcontaining the ³H₂O released by the SCD1 desaturation reaction is addedto scintillation fluid and the radioactivity measured in a PackardTopCount. The data is analysed to identify the IC₅₀ for test compoundsand reference compounds. Representative compounds of the inventionshowed activity as inhibitors of SCD when tested in this assay. Theactivity was defined in terms of % SCD enzyme activity remaining at thedesired concentration of the test compound or as the IC₅₀ concentration.

The IC₅₀ (affinity) of the example compounds toward the stearoyl-CoAdesaturase is comprised between around 20 μM and 0.0001 μM or betweenaround 5 μM and 0.0001 μM or between around 1 μM and 0.0001 μM.

Those skilled in the art are aware of a variety of modifications to thisassay that can be useful for measuring inhibition of stearoyl-CoAdesaturase activity in microsomes or in cells by test compounds.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound of formula (I):

X is CH or N; Y is NH, N—CH₃, O or S; W is —N(R⁵)C(O)—, —C(O)N(R⁵)—,—OC(O)N(R⁵)—, —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—,—S(O)_(t)—, —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,—OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,—C(═N(R^(5a)))N(R⁵)—, or a direct bond; V is —N(R⁵)C(O)—, —C(O)N(R⁵)—,—OC(O)N(R⁵)—, —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—,—S(O)_(t), —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)N(R⁵)—, —C(O)—,—OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,—C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond; n is 0, 1, 2 or 3; p is0 to 9; t is 1 or 2; R¹ is hydrogen, alkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or R¹ isa multi-ring structure having 2 to 4 rings wherein the rings areindependently cycloalkyl, heterocyclyl, aryl or heteroaryl and wheresome or all of the rings may be fused to each other; R² is hydrogen,alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; or R² is a multi-ring structure having 2to 4 rings wherein the rings are independently cycloalkyl, heterocyclyl,aryl or heteroaryl and where some or all of the rings may be fused toeach other; R³ is hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl,heteroaryl, halo, haloalkyl, haloalkyoxy, cyano or —N(R⁵)₂; each R⁴ isindependently alkyl, halo, haloalkyl, haloalkoxy, hydroxyl,hydroxyalkyl, alkoxy, —N(R⁵)₂, cycloalkylalkyl n or aralkyl; or two R⁴sattached to the same carbon form an oxo while each of the remaining R⁴sare as described above; each R⁵ is independently hydrogen, alkyl, aryl,heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl or aralkyl; andR^(5a) is hydrogen, alkyl, cycloalkylalkyl or cyano; or a stereoisomer,enantiomer or tautomer thereof, a pharmaceutically acceptable saltthereof, a pharmaceutical composition thereof or a prodrug thereof. 2.The compound according to claim 1, wherein V is ═C(R⁵)—, —N(R⁵)₂— or adirect bond; W is —N(R⁵)C(O)—, —C(O)N(R⁵)—, —C(O)O— or a direct bond; Xis N or CH; Y is S; p is 1, 2, 3, 4, 5, 6 or 7; R¹ is hydrogen, alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; R² is hydrogen, alkyl,alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;R³ is hydrogen or alkyl; and R⁵ is hydrogen or alkyl.
 3. The compoundaccording to claim 1, wherein V is a direct bond; W is —N(R⁵)C(O)— or—C(O)O—; X is N or CH; Y is S; p is 1, 2, 3, 4, 5, 6 or 7; R¹ is ofalkyl, aryl, aralkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkylor heteroarylalkyl; R² is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R³ is hydrogen or alkyl;and R⁵ is hydrogen or alkyl.
 4. The compound according to claim 1,wherein V is a direct bond; W is —N(R⁵)C(O)—; X is N or CH; Y is S; p is1, 2, 3, 4, 5, 6 or 7; n is 1 or 2; R¹ is alkyl, aryl, aralkyl orheteroaryl; R² is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl or aralkyl; R³ is alkyl; and R⁵ is hydrogen. 5.The compound according to claim 1, wherein the compound is selected fromthe group consisting of:N-Benzyl-2-(2,6-dioxo-4-phenylpiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-benzyl-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)piperidin-1-yl)thiazole-5-carboxamide;N-Benzyl-2-(3-(4-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-4-methyl-2-(3-(4-methylbenzyl)-2-oxopiperidin-1-yl)thiazole-5-carboxamide;N-Benzyl-2-(3-(3-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-(2,5-difluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-(4-methoxybenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-(hydroxy(phenyl)methyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-((5-ethylthiophen-2-yl)methylene)-2-oxopiperidin-1-yl-4-methylthiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethylene)piperidin-1-yl)thiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(3-phenylpropyl)piperidin-1-yl)thiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(pyridin-3-ylmethyl)piperidin-1-yl)thiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-phenethylpiperidin-1-yl)thiazole-5-carboxamide;N-(3-Fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)piperidin-1-yl)thiazole-5-carboxamide;N-(3-Fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-2-(3-(cyclopropylmethylamino)-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzylamino)piperidin1-yl)thiazole-5-carboxamide;N-(4-Fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide;N-(4-Fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-4-methythiazole-5-carboxamide;2-(3-(4-(Difluoromethoxy)benzyl)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;N-(4-Fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide;N-Benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide;N-Benzyl-2-(3-(4-(difluoromethoxy)benzyl)-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide;2-(3-(Cyclopropylmethyl)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;2-(3-(2-Cyclopropylethylamino)-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;N-(4-Fluorobenzyl)-2-(3-(4-fluorobenzylamino-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide;N-(4-Fluorobenzoyl)-4-methyl-2-(2-oxo-3-(3,3,3-trifluoropropylamino)pyrrolidin-1-yl)thiazole-5-carboxamide;N-Benzyl-2-(4-benzyl-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide;(S)—N-Benzyl-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide;(R)—N-Benzyl-2-(4-hydroxy-2-oxopyrrolidin-1-yl)-4-methylthiazole-5-carboxamide;2-(3-(4-Fluorobenzyl)-2-oxopyrrolidin-1-yl)-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;4-Methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)pyrrolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide;N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide;N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide;N-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide;2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;andN-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide.6. A pharmaceutical composition, comprising: the compound of formula (I)according to claim 1 and a pharmaceutically acceptable excipient orcarrier.
 7. A method of inhibiting human stearoyl-CoA desaturase (hSCD)activity, comprising: contacting a source of hSCD with a compound offormula (I):

X is CH or N; Y is NH, N—CH₃, O or S; W is —N(R⁵)C(O)—, —C(O)N(R⁵)—,—OC(O)N(R⁵)—, —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—,—S(O)_(t)—, —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,—OC(O)—, —C(O)O—, —N(R⁵)C(—N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—,—C(═N(R^(5a)))N(R⁵)—, or a direct bond; V is —N(R⁵)C(O)—, —C(O)N(R⁵)—,—OC(O)N(R⁵)—, —N(R⁵)C(O)O—, —N(R⁵)C(O)N(R⁵)—, —O—, —S—, —N(R⁵)—,—S(O)_(t), —N(R⁵)S(O)_(t)—, —S(O)_(t)N(R⁵)—, —OS(O)_(t)N(R⁵)—, —C(O)—,—OC(O)—, —C(O)O—, —N(R⁵)C(═N(R^(5a)))NR⁵—, —N(R⁵)((R^(5a))N═)C—, or—C(═N(R^(5a)))N(R⁵)—, ═C(R⁵)— or a direct bond; n is 0, 1, 2 or 3; p is0 to 9; t is 1 or 2; R¹ is hydrogen, alkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or R¹ isa multi-ring structure having 2 to 4 rings wherein the rings areindependently cycloalkyl, heterocyclyl, aryl or heteroaryl and wheresome or all of the rings may be fused to each other; R² is hydrogen,alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; or R² is a multi-ring structure having 2to 4 rings wherein the rings are independently cycloalkyl, heterocyclyl,aryl or heteroaryl and where some or all of the rings may be fused toeach other; R³ is of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl,heteroaryl, halo, haloalkyl, haloalkoxy, cyano or —N(R⁵)₂; each R⁴ isindependently alkyl, oxo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl,alkoxy, —N(R⁵)₂, cycloalkylalkyl or aralkyl; or two R⁴s attached to thesame carbon form an oxo while each of the remaining R⁴s are as describedabove; each R⁵ is independently hydrogen, alkyl, aryl, heteroaryl,cycloalkyl, hydroxyalkyl, cycloalkylalkyl or aralkyl; and R^(5a) ishydrogen, alkyl, cycloalkylalkyl or cyano; or a stereoisomer, enantiomeror tautomer thereof, a pharmaceutically acceptable salt thereof, apharmaceutical composition thereof or a prodrug thereof.
 8. A method oftreating a disease or condition mediated by stearoyl-CoA desaturase(SCD) in a mammal in need thereof, comprising: administering to themammal in need thereof a therapeutically effective amount of a thecompound of formula (I) according to claim
 1. 9. The method according toclaim 8, wherein the disease or condition is metabolic syndrome,Syndrome X, diabetes, insulin resistance, decreased glucose tolerance,non-insulin-dependent diabetes mellitus, Type II diabetes, Type Idiabetes, diabetic complications, body weight disorders, weight loss,body mass index or leptin related diseases.
 10. The method according toclaim 9, wherein the metabolic syndrome is dyslipidemia, obesity,insulin resistance, hypertension, microalbuminemia, hyperuricaemia, andhypercoagulability.
 11. The method according to claim 9, wherein thebodyweight disorder is obesity, overweight, cachexia and anorexia. 12.The method according to claim 8, where the disease or condition is askin disorder.
 13. The method according to claim 12, wherein the skindisorder is eczema, acne, psoriasis, or keloid scar formation orprevention.
 14. A pharmaceutical composition, comprising: atherapeutically effective amount of the compound of claim 1 incombination with a therapeutically effective amount of insulin, insulinderivative or mimetic; insulin secretagogue; insulinotropic sulfonylureareceptor ligand; PPAR ligand; insulin sensitizer; biguanide;alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic; DPPIVinhibitor; HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXRor LXR ligand; cholestyramine; fibrates; nicotinic acid; or aspirin.15-19. (canceled)